Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials
Identifieur interne : 000255 ( Pmc/Corpus ); précédent : 000254; suivant : 000256Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials
Auteurs : Yuan Cheng ; Cai He ; Manni Wang ; Xuelei Ma ; Fei Mo ; Shengyong Yang ; Junhong Han ; Xiawei WeiSource :
- Signal Transduction and Targeted Therapy [ 2095-9907 ] ; 2019.
Abstract
Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.
Url:
DOI: 10.1038/s41392-019-0095-0
PubMed: 31871779
PubMed Central: 6915746
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials</title><author><name sortKey="Cheng, Yuan" sort="Cheng, Yuan" uniqKey="Cheng Y" first="Yuan" last="Cheng">Yuan Cheng</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="He, Cai" sort="He, Cai" uniqKey="He C" first="Cai" last="He">Cai He</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Wang, Manni" sort="Wang, Manni" uniqKey="Wang M" first="Manni" last="Wang">Manni Wang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Ma, Xuelei" sort="Ma, Xuelei" uniqKey="Ma X" first="Xuelei" last="Ma">Xuelei Ma</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Mo, Fei" sort="Mo, Fei" uniqKey="Mo F" first="Fei" last="Mo">Fei Mo</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Yang, Shengyong" sort="Yang, Shengyong" uniqKey="Yang S" first="Shengyong" last="Yang">Shengyong Yang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Han, Junhong" sort="Han, Junhong" uniqKey="Han J" first="Junhong" last="Han">Junhong Han</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Wei, Xiawei" sort="Wei, Xiawei" uniqKey="Wei X" first="Xiawei" last="Wei">Xiawei Wei</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31871779</idno><idno type="pmc">6915746</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915746</idno><idno type="RBID">PMC:6915746</idno><idno type="doi">10.1038/s41392-019-0095-0</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000255</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000255</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials</title><author><name sortKey="Cheng, Yuan" sort="Cheng, Yuan" uniqKey="Cheng Y" first="Yuan" last="Cheng">Yuan Cheng</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="He, Cai" sort="He, Cai" uniqKey="He C" first="Cai" last="He">Cai He</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Wang, Manni" sort="Wang, Manni" uniqKey="Wang M" first="Manni" last="Wang">Manni Wang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Ma, Xuelei" sort="Ma, Xuelei" uniqKey="Ma X" first="Xuelei" last="Ma">Xuelei Ma</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Mo, Fei" sort="Mo, Fei" uniqKey="Mo F" first="Fei" last="Mo">Fei Mo</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Yang, Shengyong" sort="Yang, Shengyong" uniqKey="Yang S" first="Shengyong" last="Yang">Shengyong Yang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Han, Junhong" sort="Han, Junhong" uniqKey="Han J" first="Junhong" last="Han">Junhong Han</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Wei, Xiawei" sort="Wei, Xiawei" uniqKey="Wei X" first="Xiawei" last="Wei">Xiawei Wei</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Signal Transduction and Targeted Therapy</title><idno type="ISSN">2095-9907</idno><idno type="eISSN">2059-3635</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Signal Transduct Target Ther</journal-id><journal-id journal-id-type="iso-abbrev">Signal Transduct Target Ther</journal-id><journal-title-group><journal-title>Signal Transduction and Targeted Therapy</journal-title></journal-title-group><issn pub-type="ppub">2095-9907</issn><issn pub-type="epub">2059-3635</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31871779</article-id><article-id pub-id-type="pmc">6915746</article-id><article-id pub-id-type="publisher-id">95</article-id><article-id pub-id-type="doi">10.1038/s41392-019-0095-0</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review Article</subject></subj-group></article-categories><title-group><article-title>Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Cheng</surname><given-names>Yuan</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>He</surname><given-names>Cai</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Manni</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Ma</surname><given-names>Xuelei</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Mo</surname><given-names>Fei</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Shengyong</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Han</surname><given-names>Junhong</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Wei</surname><given-names>Xiawei</given-names></name><address><email>xiaweiwei@scu.edu.cn</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0807 1581</institution-id><institution-id institution-id-type="GRID">grid.13291.38</institution-id><institution>Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital,</institution><institution>Sichuan University,</institution></institution-wrap>Chengdu, China</aff></contrib-group><pub-date pub-type="epub"><day>17</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>17</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>4</volume><elocation-id>62</elocation-id><history><date date-type="received"><day>14</day><month>7</month><year>2019</year></date><date date-type="rev-recd"><day>16</day><month>10</month><year>2019</year></date><date date-type="accepted"><day>24</day><month>10</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Drug development</kwd><kwd>Cancer epidemiology</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China (National Science Foundation of China)</institution></institution-wrap></funding-source><award-id>No. 81602950</award-id><principal-award-recipient><name><surname>Wei</surname><given-names>Xiawei</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution>National Key Research and Development Program of China (No. 2016YFA0201402)</institution></funding-source></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Introduction</title><p id="Par2">After the discovery of DNA and the double helix structure, classic genetics has long assumed that the sequences of DNA determine the phenotypes of cells. DNA is packaged as chromatin in cells, with nucleosomes being the fundamental repeating unit. Four core histones (H2A, H2B, H3, and H4) form an octamer and are then surrounded by a 147-base-pair (bp) segment of DNA. Nucleosomes are separated by 10–60 bp DNA. Researchers have gradually found organisms that share the same genetic information but have different phenotypes, such as somatic cells from the same individual that share a genome but function completely differently. The term epigenetics was first proposed and established in 1942 when Conrad Waddington tried to interpret the connection between genotype and phenotype.<sup><xref ref-type="bibr" rid="CR1">1</xref></sup> Later, Arthur Riggs and his group interpreted epigenetics as inherited differences in mitosis and meiosis, which could explain the changes in phenotypes. They were both trying to find the link between genotype and phenotype. Epigenetics is usually referred to as a genomic mechanism that reversibly influences gene expression without altering DNA sequences. Holliday assumed that epigenetics was also mitotically and/or meiotically heritable without DNA sequence change. Aberrant DNA methylation could be repaired via meiosis, but some patterns are still transmitted to offspring.<sup><xref ref-type="bibr" rid="CR2">2</xref></sup> This phenomenon covers a wide range of cellular activities, such as cell growth, differentiation, and disease development, and is heritable.<sup><xref ref-type="bibr" rid="CR3">3</xref></sup> Generally, epigenetic events involve DNA methylation, histone modification, the readout of these modifications, chromatin remodeling and the effects of noncoding RNA. The elements involved in different modification patterns can be divided into three roles, “writer,” “reader,” and “eraser”. The “writers” and “erasers” refer to enzymes that transfer or remove chemical groups to or from DNA or histones, respectively. “Readers” are proteins that can recognize the modified DNA or histones (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). To coordinate multiple biological processes, the epigenome cooperates with other regulatory factors, such as transcription factors and noncoding RNAs, to regulate the expression or repression of the genome. Epigenetics can also be influenced by cellular signaling pathways and extracellular stimuli. These effects are temporary and yet long-standing. Given the importance of epigenetics in influencing cell functions, a better understanding of both normal and abnormal epigenetic processes can help to understand the development and potential treatment of different types of diseases, including cancer.<fig id="Fig1"><label>Fig. 1</label><caption><title>Epigenetic regulation of DNA methylation, histone acetylation, and histone methylation.</title><p>Gene silencing in mammalian cells is usually caused by methylation of DNA CpG islands together with hypoacetylated and hypermethylated histones. The “writers” (DNMTs, HATs, and HMTs) and “erasers” (DNA-demethylating enzymes, HDACs, and KDMs) are enzymes responsible for transferring or removing chemical groups to or from DNA or histones; MBDs and other binding proteins are “readers” that recognize methyl-CpGs and modified histones. DNMTs, DNA methyltransferases; MBDs, methyl-CpG binding domain proteins; HATs, histone acetylases; HDACs, histone deacetylases; HMTs, histone methyltransferases; KDMs, histone-demethylating enzymes.</p></caption><graphic xlink:href="41392_2019_95_Fig1_HTML" id="d29e290"></graphic></fig></p><p id="Par3">The etiology of cancer is quite complicated and involves both environmental and hereditary influences. In cancer cells, the alteration of genomic information is usually detectable. Like genome instability and mutation, epigenome dysregulation is also pervasive in cancer (Fig. <xref rid="Fig2" ref-type="fig">2</xref>). Some of the alterations determine cell function and are involved in oncogenic transformation.<sup><xref ref-type="bibr" rid="CR4">4</xref></sup> However, by reversing these mutations by drugs or gene therapy, the phenotype of cancer can revert to normal. Holliday proposed a theory that epigenetic changes are responsible for tumorigenesis. The alteration of cellular methylation status by a specific methyltransferase might explain the differences in the probability of malignant transformation.<sup><xref ref-type="bibr" rid="CR5">5</xref></sup> In clinical settings, we noticed that although cancer patients share the same staging and grade, they present totally different outcomes. In tumor tissues, different tumor cells show various patterns of histone modification, genome-wide or in individual genes, indicating that epigenetic heterogeneity exists at a cellular level.<sup><xref ref-type="bibr" rid="CR6">6</xref></sup> Likewise, using molecular biomarkers is thought to be a potential method to divide patients into different groups. It is important to note that tumorigenesis is the consequence of the combined action of multiple epigenetic events. For example, the repression of tumor suppressor genes is usually caused by methylation of DNA CpG islands together with hypoacetylated and hypermethylated histones.<sup><xref ref-type="bibr" rid="CR7">7</xref></sup> During gene silencing, several hallmarks of epigenetic events have been identified, including histone H3 and H4 hypoacetylation, histone H3K9 methylation, and cytosine methylation.<sup><xref ref-type="bibr" rid="CR8">8</xref>,<xref ref-type="bibr" rid="CR9">9</xref></sup><fig id="Fig2"><label>Fig. 2</label><caption><title>Epigenetic regulations in cancer.</title><p>Alterations in epigenetic modifications in cancer regulate various cellular responses, including cell proliferation, apoptosis, invasion, and senescence. Through DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, epigenetics play an important role in tumorigenesis. These main aspects of epigenetics present reversible effects on gene silencing and activation via epigenetic enzymes and related proteins. DNMTs, DNA methyltransferases; TETs, ten-eleven translocation enzymes; HATs, histone acetylases; HDACs, histone deacetylases; HMTs, histone methyltransferases; HDMs, histone-demethylating enzymes. MLL, biphenotypic (mixed lineage) leukemia.</p></caption><graphic xlink:href="41392_2019_95_Fig2_HTML" id="d29e329"></graphic></fig></p><p id="Par4">Therefore, epigenetics enables us to investigate the potential mechanism underlying cancer phenotypes and provides potential therapy options. In this review, we focused and briefly expanded on three aspects of epigenetics in cancer: DNA methylation, histone acetylation and histone methylation. Finally, we summarized the current developments in epigenetic therapy for cancers.</p></sec><sec id="Sec2"><title>DNA methylation</title><p id="Par5">The DNA methylation pattern in mammals follows certain rules. Germ cells usually go through a stepwise demethylation to ensure global repression and suitable gene regulation during embryonic development. After implantation, almost all CpGs experience de novo methylation except for those that are protected.<sup><xref ref-type="bibr" rid="CR10">10</xref></sup> Normal dynamic changes in DNA methylation and demethylation based on altered expression of enzymes have been known to be associated with aging.<sup><xref ref-type="bibr" rid="CR11">11</xref>,<xref ref-type="bibr" rid="CR12">12</xref></sup> However, inappropriate methylation of DNA can result in multiple diseases, including inflammatory diseases, precancerous lesions, and cancer.<sup><xref ref-type="bibr" rid="CR13">13</xref>–<xref ref-type="bibr" rid="CR15">15</xref></sup> Of note, de novo methylation of DNA in cancer serves to prevent reactivation of repressed genes rather than inducing gene repression.<sup><xref ref-type="bibr" rid="CR16">16</xref></sup> Because researchers have found that over 90% of genes undergoing de novo methylation in cancer are already in a repressed status in normal cells.<sup><xref ref-type="bibr" rid="CR17">17</xref></sup> Nevertheless, aberrant DNA methylation is thought to serve as a hallmark in cancer development by inactivating gene transcription or repressing gene transcription and affecting chromatin stability.<sup><xref ref-type="bibr" rid="CR18">18</xref></sup></p><p id="Par6">The precise mechanism by which DNA methylation affects chromatin structure unclear, but it is known that methyl-DNA is closely associated with a closed chromatin structure, which is relatively inactive.<sup><xref ref-type="bibr" rid="CR19">19</xref></sup> Hypermethylation of promoters and hypomethylation of global DNA are quite common in cancer. It is widely accepted that gene promoters, especially key tumor suppressor genes, are unmethylated in normal tissues and highly methylated in cancer tissues.<sup><xref ref-type="bibr" rid="CR20">20</xref></sup> P16, a tumor suppressor encoded by CDKN2A, has been found to gain de novo methylation in ~20% of different primary neoplasms.<sup><xref ref-type="bibr" rid="CR21">21</xref></sup> Mutations in important and well-studied tumor-suppressive genes, such as P53 and BRCA1, are frequently identified in multiple cancers.<sup><xref ref-type="bibr" rid="CR22">22</xref>–<xref ref-type="bibr" rid="CR24">24</xref></sup> Studies have found that the level of methylation is positively associated with tumor size. In support of this, a whole-genome methylation array analysis in breast cancer patients found significantly increased CpG methylation in FES, P2RX7, HSD17B12, and GSTM2 coincident with increasing tumor stage and size.<sup><xref ref-type="bibr" rid="CR25">25</xref></sup> After analysis of long-range epigenetic silencing at chromosome 2q14.2, methylation of EN1 and SCTR, the first well-studied example of coordinated epigenetic modification, was significantly increased in colorectal and prostate cancers.<sup><xref ref-type="bibr" rid="CR26">26</xref>,<xref ref-type="bibr" rid="CR27">27</xref></sup> EN1 methylation has also been observed to be elevated by up to 60% in human salivary gland adenoid cystic carcinoma.<sup><xref ref-type="bibr" rid="CR28">28</xref></sup> Of note, only ~1% of normal samples exhibited EN1 CpG island hypermethylation.<sup><xref ref-type="bibr" rid="CR26">26</xref></sup> Therefore, the significant difference between cancer cells and normal cells makes EN1 a potential cancer marker in diagnosis. In human pancreatic cancer, the APC gene, encoding a regulator of cell junctions, is hypermethylated by DNMT overexpression.<sup><xref ref-type="bibr" rid="CR29">29</xref></sup> During an analysis of colorectal disease methylation patterns, researchers found several genes that showed significant changes between precancerous diseases and cancers, including RUNX3, NEUROG1, CACNA1G, SFRP2, IGF2 DMR0, hMLH1, and CDKN2A.<sup><xref ref-type="bibr" rid="CR30">30</xref></sup> In the human colon cancer cell line HCT116, hMLH1 and CDKN2A always bear genetic mutation and hypermethylation of one allele, and this leads to inactivation of key tumor suppressors.<sup><xref ref-type="bibr" rid="CR31">31</xref></sup> It is known that p16, p15, and pax6 are usually aberrantly methylated in bladder cancer and show enhanced methylation in cell culture.<sup><xref ref-type="bibr" rid="CR32">32</xref></sup>. Unlike gene promoter methylation, gene body methylation usually results in increased transcriptional activity.<sup><xref ref-type="bibr" rid="CR33">33</xref></sup> This process often occurs in CpG-poor areas and causes a base transition from C to T.<sup><xref ref-type="bibr" rid="CR34">34</xref></sup> The hypermethylation of specific CpG islands in cancer tissues is informative of mutations when the gene in normal tissues is unmethylated. One representative marker is glutathione S-transferase-π (GSTP1), which is still the most common alteration in human prostate cancer.<sup><xref ref-type="bibr" rid="CR35">35</xref></sup> Recently, DNA methylation in cancer has generally been associated with drug resistance and predicting response to treatment.<sup><xref ref-type="bibr" rid="CR36">36</xref></sup> For example, MGMT (O-6-methylguanine DNA methyltransferase) hypermethylation is still the best independent predictor of response to BCNU (carmustine) and temozolomide in gliomas because hypermethylation of MGMT makes tumor cells more sensitive to treatments and is associated with regression of tumor and prolonged overall survival.<sup><xref ref-type="bibr" rid="CR37">37</xref>,<xref ref-type="bibr" rid="CR38">38</xref></sup> Similarly, MGMT is also a useful predictor of response to cyclophosphamide in diffuse large B-cell lymphoma<sup><xref ref-type="bibr" rid="CR39">39</xref></sup> (Table <xref rid="Tab1" ref-type="table">1</xref>).<table-wrap id="Tab1"><label>Table 1</label><caption><p>Key regulatory factors of DNA methylation in cancer.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Enzyme</th><th>Roles in cancer</th><th>Cancer type</th><th>Associated biological process (involved mechanism and molecules)</th></tr></thead><tbody><tr><td colspan="4"><italic>DNA methyltransferases</italic></td></tr><tr><td colspan="4">DNMT1: DNMT1 is responsible for maintenance of DNA methylation and is expressed at high concentrations in dividing cells to guard existing methylated sites.</td></tr><tr><td></td><td>Promoter</td><td>AML, CML, cervical cancer, colorectal cancer, glioma, lung cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, breast cancer, esophageal cancer, bladder cancer, prostate cancer, thyroid cancer, ovarian cancer<sup><xref ref-type="bibr" rid="CR92">92</xref>–<xref ref-type="bibr" rid="CR100">100</xref></sup></td><td>Promotes EMT phenotype, cell apoptosis, cell proliferation, migration, cancer stemness, and cisplatin sensitivity (β-catenin, E-cadherin, PTEN, p18, p27, P21, P16, miR-124, miR-148a, miR-152, miR-185, miR-506), DNMT1 is also upregulated by <italic>Helicobacter pylori</italic> CagA</td></tr><tr><td></td><td>Suppressor</td><td>Prostate cancer, cervical cancer<sup><xref ref-type="bibr" rid="CR101">101</xref>,<xref ref-type="bibr" rid="CR102">102</xref></sup></td><td>Cell migration, EMT and stem cell potential</td></tr><tr><td colspan="4">DNMT3a: DNMT3a methylates unmethylated DNA de novo and is required for maternal imprinting at different methylated regions.</td></tr><tr><td></td><td>Promoter</td><td>Cervical cancer, CML, breast cancer, gastric cancer, prostate cancer, ovarian cancer, bone cancer, testicular cancer<sup><xref ref-type="bibr" rid="CR52">52</xref>,<xref ref-type="bibr" rid="CR103">103</xref>–<xref ref-type="bibr" rid="CR107">107</xref></sup></td><td>Promotes cell proliferation and invasion. (VEGFA, Wnt/β-catenin signaling, miR-182, miR-708-5p)</td></tr><tr><td></td><td>Suppressor</td><td>Lymphoma, AML, breast cancer, colorectal cancer, lung cancer<sup><xref ref-type="bibr" rid="CR108">108</xref>–<xref ref-type="bibr" rid="CR110">110</xref></sup></td><td>Low level of DNMT3a is associated with the poor survival of cancer patients and promotes tumor progression but not initiation</td></tr><tr><td colspan="4">DNMT3b: DNMT3b is also responsible for de novo methylation and is required for methylation of centromeric minor satellite repeats and CGIs in inactive X chromosomes.</td></tr><tr><td></td><td>Promoter</td><td>CML, AML, glioma, lung cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, pancreatic cancer, bladder cancer, cervical cancer<sup><xref ref-type="bibr" rid="CR52">52</xref>,<xref ref-type="bibr" rid="CR94">94</xref>,<xref ref-type="bibr" rid="CR111">111</xref>–<xref ref-type="bibr" rid="CR113">113</xref></sup></td><td>Promotes cell proliferation, and invasion and the chemotherapy effects of cisplatin; is associated with poor prognosis (E-cadherin, PTEN, P21, P16, miR-29b, miR-124, miR-506)</td></tr><tr><td></td><td>Suppressor</td><td>AML, bladder cancer<sup><xref ref-type="bibr" rid="CR109">109</xref>,<xref ref-type="bibr" rid="CR114">114</xref></sup></td><td>Downregulation of DNMT3a is associated with poor prognosis</td></tr><tr><td colspan="4"><italic>Methyl-CpG binding proteins</italic></td></tr><tr><td>MeCP2</td><td>Promoter</td><td>Prostate cancer, colorectal cancer, breast cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR115">115</xref>,<xref ref-type="bibr" rid="CR116">116</xref></sup></td><td>Promotes cell proliferation, invasion, metastasis, apoptosis, cell cycle arrest in the G0/G1 phase, chemotherapy effects, regulation of estrogen receptor status, involves the MEK1/2-ERK1/2 signaling pathway (miR-638, miR-212)</td></tr><tr><td></td><td>Suppressor</td><td>Pancreatic cancer<sup><xref ref-type="bibr" rid="CR117">117</xref></sup></td><td>Decreased expression of MeCP2 contributes to cancer development</td></tr><tr><td>MBD1</td><td>Promoter</td><td>Pancreatic cancer, prostate cancer<sup><xref ref-type="bibr" rid="CR118">118</xref>,<xref ref-type="bibr" rid="CR119">119</xref></sup></td><td>Promotes cell EMT, proliferation, invasion, and metastasis and the chemoradioresistance of cancer cells and induces an antioxidant response (E-cadherin)</td></tr><tr><td>MBD2</td><td>Promoter</td><td>Lung cancer, colon cancer, breast cancer, prostate cancer<sup><xref ref-type="bibr" rid="CR94">94</xref>,<xref ref-type="bibr" rid="CR120">120</xref>–<xref ref-type="bibr" rid="CR122">122</xref></sup></td><td>Promotes cell invasion and metastasis (p14)</td></tr><tr><td>MBD4</td><td>Promoter</td><td>Colon cancer, breast cancer<sup><xref ref-type="bibr" rid="CR123">123</xref>,<xref ref-type="bibr" rid="CR124">124</xref></sup></td><td>Causes dominant negative impairment of DNA repair</td></tr><tr><td>KAISO (ZBTB33)</td><td>Promoter</td><td>Colon cancer, cervical cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, and chronic myeloid leukemia<sup><xref ref-type="bibr" rid="CR125">125</xref>–<xref ref-type="bibr" rid="CR128">128</xref></sup></td><td>Silencing of tumor suppressor genes, EMT, apoptosis, migration and invasion (Wnt/β-catenin, TGFβ, EGFR, Notch, miR-4262, miR-31)</td></tr><tr><td>ZBTB4</td><td>Suppressor</td><td>Breast cancer, Ewing sarcoma, prostate cancer, bladder cancer<sup><xref ref-type="bibr" rid="CR77">77</xref>,<xref ref-type="bibr" rid="CR129">129</xref>–<xref ref-type="bibr" rid="CR131">131</xref></sup></td><td>Promotes cell growth and apoptosis and controls the cellular response to p53 activation, promoting long-term cell survival (miR-17-92/106b-25</td></tr><tr><td>ZBTB38</td><td>Promoter</td><td>Bladder cancer<sup><xref ref-type="bibr" rid="CR132">132</xref></sup></td><td>Promotes cell migration and invasion (Wnt/β‑catenin pathway)</td></tr><tr><td>UHRF1</td><td>Promoter</td><td>Hepatocellular carcinoma, bladder cancer, renal cell carcinoma, lung cancer, retinoblastoma, intrahepatic cholangiocarcinoma, colon cancer, pancreatic cancer, gastric cancer, prostate cancer, melanoma, hepatoblastoma, esophageal squamous cell carcinoma, cervical cancer, breast cancer, thyroid cancer<sup><xref ref-type="bibr" rid="CR133">133</xref>–<xref ref-type="bibr" rid="CR138">138</xref></sup></td><td>Promotes cell proliferation, EMT, and viability, increases hypoxia inducible factor (HIF)1α, CSCs, taxane resistance correlates with poor pathological characteristics, human papillomavirus (HPV) contributes to overexpression of UHRF1 (miR-101, miR-124, PI3K/Akt signaling pathway, MEK/ERK pathway)</td></tr><tr><td>UHRF2</td><td>Promoter</td><td>Intrahepatic cholangiocarcinoma, hepatocellular carcinoma, colon cancer<sup><xref ref-type="bibr" rid="CR139">139</xref>,<xref ref-type="bibr" rid="CR140">140</xref></sup></td><td>Promotes cell migration and invasion, and is associated with lower disease-free survival</td></tr><tr><td></td><td>suppressor</td><td>Colon cancer, lung cancer, esophageal carcinoma<sup><xref ref-type="bibr" rid="CR141">141</xref>,<xref ref-type="bibr" rid="CR142">142</xref></sup></td><td>Low level of UHRF2 is associated with shorter overall survival, vascular invasion and poor prognosis</td></tr><tr><td colspan="4"><italic>DNA demethylases</italic></td></tr><tr><td colspan="4">TET1: TET1 is highly expressed in mouse embryonic stem cells, the inner cell mass of blastocysts, and developing PGCs.</td></tr><tr><td></td><td>Promoter</td><td>MLL-rearranged leukemia, AML, breast cancer, ovarian cancer, lung cancer, renal cancer<sup><xref ref-type="bibr" rid="CR143">143</xref>–<xref ref-type="bibr" rid="CR147">147</xref></sup></td><td>TET1-MLL fusion, cell migration, anchorage-independent growth, cancer stemness, and tumorigenicity, prevention of senescence via loss of p53, associated with a worse overall survival and sensitivity to drugs (PI3K-mTOR pathway)</td></tr><tr><td></td><td>Suppressor</td><td>Hematopoietic malignancy, hepatocellular carcinoma, prostate cancer, colon cancer, gastric cancer, breast cancer, nasopharyngeal carcinoma cells, ovarian cancer<sup><xref ref-type="bibr" rid="CR90">90</xref>,<xref ref-type="bibr" rid="CR148">148</xref>,<xref ref-type="bibr" rid="CR149">149</xref></sup></td><td>Promotes EMT and increases cancer cell growth, migration, and invasion (miR-21-5p, Wnt/β-catenin signaling pathway, AKT and FAK pathways)</td></tr><tr><td colspan="4">TET2/TET3: TET2 and TET3 are present in multiple mouse adult tissues, whereas only TET3 is present in mouse oocytes and one-cell zygotes</td></tr><tr><td>TET2</td><td>Suppressor</td><td>MDS, AML, CML, prostate cancer, gastric cancer, breast cancer, colorectal cancer, ovarian cancer, hepatocellular carcinoma, leukemia<sup><xref ref-type="bibr" rid="CR87">87</xref>,<xref ref-type="bibr" rid="CR150">150</xref>–<xref ref-type="bibr" rid="CR153">153</xref></sup></td><td>Promotes cell proliferation, colony formation, metastasis, is associated with reduced patient survival, pathologic stage, tumor grading, lymph node metastasis, and vascular thrombosis (caspase-4, ET2/E-cadherin/β-catenin regulatory loop)</td></tr><tr><td>TET3</td><td>Promoter</td><td>Renal cell carcinoma<sup><xref ref-type="bibr" rid="CR154">154</xref></sup></td><td>Acts as an independent predictor of poor outcome</td></tr><tr><td></td><td>Suppressor</td><td>Head and neck cancer, ovarian cancer, breast cancer<sup><xref ref-type="bibr" rid="CR155">155</xref>,<xref ref-type="bibr" rid="CR156">156</xref></sup></td><td>Is associated with EMT, overall survival, disease-free survival (miR-30d)</td></tr></tbody></table><table-wrap-foot><p><italic>AML</italic> acute myeloid leukemia, <italic>CML</italic> chronic myeloid leukemia, <italic>EMT</italic> epithelial-mesenchymal transition, <italic>VEGFR</italic> vascular endothelial growth factor receptor</p></table-wrap-foot></table-wrap></p><sec id="Sec3"><title>DNA methyltransferases (DNMTs)</title><p id="Par7">DNA methylation is a covalent modification of DNA and is one of the best-studied epigenetic markers. It plays an important role in normal cell physiology in a programmed manner. The best-known type of DNA methylation is methylation of cytosine (C) at the 5th position of its carbon ring (5-mC), especially at a C followed by a guanine (G), so-called CpG sites. Non-CpG methylation, such as methylation of CpA (adenine) and CpT (thymine), is not common and usually has restricted expression in mammals.<sup><xref ref-type="bibr" rid="CR40">40</xref></sup> CpG islands traverse ~60% of human promoters, and methylation at these sites results in obvious transcriptional regression.<sup><xref ref-type="bibr" rid="CR41">41</xref></sup> Meanwhile, among the ~28 million CpGs in the human genome in somatic cells, 60–80% are methylated in a symmetric manner and are frequently found in promoter regions.<sup><xref ref-type="bibr" rid="CR42">42</xref>,<xref ref-type="bibr" rid="CR43">43</xref></sup> The process of DNA methylation is regulated by the DNA methyltransferase (DNMT) family via the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to cytosine.<sup><xref ref-type="bibr" rid="CR44">44</xref></sup> There are five members of the DNMT family: DNMT1, DNMT2, DNMT3a, DNMT3b, and DNMT3L. DNMT1 is responsible for the maintenance of methyl-DNA, recognizes hemimethylated DNA strands and regenerates the fully methylated DNA state of DNA during cell division.<sup><xref ref-type="bibr" rid="CR45">45</xref></sup> In a recent study, DNMT1 with Stella, a factor essential for female fertility, was responsible for the establishment of the oocyte methylome during early embryo development.<sup><xref ref-type="bibr" rid="CR46">46</xref></sup> DNMT3a and DNMT3b are regarded as de novo methylation enzymes that target unmethylated CpG dinucleotides and establish new DNA methylation patterns, but they have nonoverlapping functions during different developmental stages.<sup><xref ref-type="bibr" rid="CR47">47</xref>,<xref ref-type="bibr" rid="CR48">48</xref></sup> DNMT2 and DNMT3L are not regarded as catalytically active DNA methyltransferases. DNMT2 functions as an RNA methyltransferase, while DNMT3L contains a truncated inactive catalytic domain and acts as an accessory partner to stimulate the de novo methylation activity of DNMT3A. The DNA methyltransferase-like protein DNMT3L can modulate DNMT3a activity as a stimulatory factor.<sup><xref ref-type="bibr" rid="CR49">49</xref></sup></p><p id="Par8">During aberrant DNA methylation, DNMTs play an important role. Compared with DNMT1 and DNMT3a, DNMT3b was significantly overexpressed in tumor tissues.<sup><xref ref-type="bibr" rid="CR50">50</xref></sup> Overexpression of DNMT1, DNMT3a, and DNMT3b has been observed in multiple cancers, including AML, CML, glioma, and breast, gastric, colorectal, hepatocellular, pancreatic, prostate, and lung cancers. In cervical cancer patients, DNMT1 was expressed in more than 70% of cancer cells, whereas only 16% of normal cells expressed DNMT1. The higher level of DNMT1 expression was also associated with worse prognosis.<sup><xref ref-type="bibr" rid="CR51">51</xref></sup> The expression of DNMT1, DNMT3a, and DNMT3b has been observed to be elevated in acute myeloid leukemia (AML) and various solid cancers. These three methyltransferases do not show significant changes in the chronic phase of chronic myeloid leukemia (CML), but they are significantly increased during progression to the acute phase in CML.<sup><xref ref-type="bibr" rid="CR52">52</xref>,<xref ref-type="bibr" rid="CR53">53</xref></sup> Notably, downregulation of DNMTs can also lead to tumorigenesis (Table <xref rid="Tab1" ref-type="table">1</xref>).</p></sec><sec id="Sec4"><title>Methyl-CpG recognition proteins</title><p id="Par9">How DNA methylation leads to gene repression has been considered in many studies. Several hypotheses have been proposed. Three methyl-CpG binding domain protein (MeCP) families can read the established methylated DNA sequences and in turn recruit histone deacetylases, a group of enzymes responsible for repressive epigenetic modifications, to inhibit gene expression and maintain genome integrity.<sup><xref ref-type="bibr" rid="CR10">10</xref>,<xref ref-type="bibr" rid="CR54">54</xref></sup> The first group is methyl-CpG binding domain (MBD) proteins, including MeCP2, MBD1, MBD2, and MBD4. MeCP1 is a complex containing MBD2, the histone deacetylase (HDAC) proteins HDAC1 and HDAC2, and the RbAp46 and RbAp48 proteins (also known as RBBP7 and RBBP4).<sup><xref ref-type="bibr" rid="CR55">55</xref></sup> MBD3 is unlike the other four family members and is not capable of binding to methylated DNA but instead binds to hydroxymethylated DNA.<sup><xref ref-type="bibr" rid="CR56">56</xref></sup> The zinc-finger and BTB domain-containing protein family is the second group and comprises three structurally different proteins, KAISO (ZBTB33), ZBTB4 and ZBTB38, which bind to methylated DNA via zinc-finger motifs. The third family includes two ubiquitin-like proteins with PHD and RING finger domains, UHRF1 and UHRF2, which recognize 5-mC via RING finger-associated (SRA) domains. On the other hand, methylation of DNA can also be a barrier for certain transcription factors to bind to promoter sites such as <italic>AP-2</italic>, <italic>c-Myc</italic>, <italic>CREB/ATF</italic>, <italic>E2F</italic>, and <italic>NF-kB</italic>.<sup><xref ref-type="bibr" rid="CR13">13</xref></sup></p><p id="Par10">As for methyl-group binding proteins, many studies have investigated their roles in various cancers, but the mechanism underlying these alterations remains unclear. MBD proteins cooperate with other proteins to regulate gene transcription.<sup><xref ref-type="bibr" rid="CR57">57</xref>,<xref ref-type="bibr" rid="CR58">58</xref></sup> However, the role of MBD1 and MBD2 has not been identified in human lung or colon cancer, with only limited mutations being detected.<sup><xref ref-type="bibr" rid="CR59">59</xref></sup> Furthermore, loss of MBD1 did not show any carcinogenic effect in <italic>MBD−/</italic>− mice.<sup><xref ref-type="bibr" rid="CR60">60</xref></sup> Compared with MBD1, MBD2 shows more effect on tumorigenesis. Deficiency of MBD2 strongly suppresses intestinal tumorigenesis in <italic>APC</italic><sup><italic>Min</italic></sup>-background mice.<sup><xref ref-type="bibr" rid="CR61">61</xref></sup> A possible reason is that many important signaling pathways are downregulated in colorectal cancer, and loss of MBD2 leads to reexpression of these genes.<sup><xref ref-type="bibr" rid="CR62">62</xref></sup> Meanwhile, inhibition of MBD2 shows promising effects on suppression of the tumorigenesis of human lung cancer and colon cancer.<sup><xref ref-type="bibr" rid="CR63">63</xref></sup> Although MBD3 does not directly bind to methylated DNA, it regulates the methylation process via interactions with other proteins, such as MBD2 and HDAC. For example, application of an HDAC inhibitor in lung cancer cells upregulated p21 (also known as CDKN1A) and downregulated ErbB2, leading to inhibition of cancer cell growth. Silencing of MBD3 blocked the effects of an HDAC inhibitor.<sup><xref ref-type="bibr" rid="CR64">64</xref></sup> MBD3 and MBD2 form a complex, nucleosome remodeling and deacetylase (NuRD), which interacts with histone-demethylating enzymes to regulate gene expression in cancer.<sup><xref ref-type="bibr" rid="CR65">65</xref></sup> Mutation of MBD4 has been found in colorectal cancer, endometrial carcinoma and pancreatic cancer.<sup><xref ref-type="bibr" rid="CR66">66</xref></sup> Furthermore, this mutation unexpectedly affects the stability of the whole genome, not only CpG sites.<sup><xref ref-type="bibr" rid="CR67">67</xref></sup> Knockout of MBD4 indeed increased tumorigenesis in <italic>APC</italic><sup><italic>Min</italic></sup>-background mice, which makes MBD4 a tumor suppressor.<sup><xref ref-type="bibr" rid="CR68">68</xref></sup> MBD4 is important in DNA damage repair, given the interaction between MBD4 and MMR.<sup><xref ref-type="bibr" rid="CR69">69</xref></sup> In contrast, the expression of MeCP2 and the UHRF family tends to promote tumor growth.<sup><xref ref-type="bibr" rid="CR70">70</xref>–<xref ref-type="bibr" rid="CR74">74</xref></sup> In the KAISO family, KAISO directly binds to p120<sup>ctn</sup>, a protein with an alternative location in some cancer cells, and they together regulate cell adhesion and motility.<sup><xref ref-type="bibr" rid="CR75">75</xref>,<xref ref-type="bibr" rid="CR76">76</xref></sup> However, deficiency of ZBTB4 contributes to tumorigenesis<sup><xref ref-type="bibr" rid="CR77">77</xref></sup> (Table <xref rid="Tab1" ref-type="table">1</xref>).</p></sec><sec id="Sec5"><title>DNA-demethylating enzymes</title><p id="Par11">DNA methylation is a stable and highly conserved epigenetic modification of DNA in many organisms.<sup><xref ref-type="bibr" rid="CR78">78</xref></sup> However, loss of 5-mC and DNA demethylation have been identified in different biologic processes. For example, DNA demethylation is important for primordial germ cells (PGCs) to gain pluripotent ability.<sup><xref ref-type="bibr" rid="CR79">79</xref>,<xref ref-type="bibr" rid="CR80">80</xref></sup> DNA demethylation is actively regulated by the TET protein family (ten-eleven translocation enzymes, TET1-3) via the removal of a methyl group from 5-mC. These three proteins differ from each other in terms of expression depending on the developmental stage and cell type.<sup><xref ref-type="bibr" rid="CR18">18</xref></sup> TETs oxidize 5-mC in an iterative manner and catalyze the conversion of 5-mC to 5-hydroxymethylcytosine (5-hmC), which is a key intermediate in the demethylation process.<sup><xref ref-type="bibr" rid="CR81">81</xref></sup> 5-hmC, as a relatively stable intermediate substrate, is less prone to further oxidation by TET proteins than 5-mC.<sup><xref ref-type="bibr" rid="CR82">82</xref></sup> However, overexpression of only TET1 and TET2 can cause a global decrease of 5-mC.<sup><xref ref-type="bibr" rid="CR18">18</xref></sup> Stepwise oxidation of 5-hmC by TET proteins can yield two products: 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC).<sup><xref ref-type="bibr" rid="CR83">83</xref></sup> These two molecules can be excised by thymine-DNA glycosylase (TDG) and eventually be repaired to unmodified C.<sup><xref ref-type="bibr" rid="CR84">84</xref></sup> DNA demethylation or restoration of the unmodified cytosine can also occur passively through replication-dependent dilution of 5-mC.</p><p id="Par12">Disruption of normal DNA demethylation is thought to be associated with oncogenesis. TET proteins were initially associated with leukemia. Researchers have found that in a small number of AML patients, TET1 is fused to MLL via the chromosome translocation t(10;11)(q22;q23).<sup><xref ref-type="bibr" rid="CR85">85</xref></sup> Further studies found that TET2 was more widely expressed in different tissues than TET1 and TET3. Analyses revealed that mutation or deficiency of TET2 occurred in ~15% of patients with myeloid cancers, including myelodysplastic syndrome (MDS), myeloproliferative disorders, and AML.<sup><xref ref-type="bibr" rid="CR86">86</xref></sup> In patients with CML, mutation of TET2 has been detected in ~50% of patients.<sup><xref ref-type="bibr" rid="CR87">87</xref></sup> Although TET2 mutations have been found in several myeloid malignancies, their prognostic effect remains controversial. Based on the phenomenon that mutation of TET2 was elevated in patients whose disease transformed from chronic myeloid malignancy to AML, researchers considered that TET2 loss was important for cells to regain the ability to self-renew.<sup><xref ref-type="bibr" rid="CR88">88</xref></sup> The role of TET proteins has also been investigated in several solid tumors. Compared with surrounding normal tissues, 5-hmC is significantly reduced in human breast, liver, lung, pancreatic, and prostate cancers with reduced expression of TET family proteins.<sup><xref ref-type="bibr" rid="CR89">89</xref></sup> Deficiency of TET1 in prostate and breast cancer is associated with tumor cell invasion and breast xenograft tumor formation via the inhibition of the methylation of metalloproteinase (TIMP) family proteins 2 and 3.<sup><xref ref-type="bibr" rid="CR90">90</xref></sup> Loss of 5-hmC is an epigenetic hallmark of melanoma, and thus, introducing TET2 into melanoma cells results in suppression of tumor growth and increased survival in an animal model<sup><xref ref-type="bibr" rid="CR91">91</xref></sup> (Table <xref rid="Tab1" ref-type="table">1</xref>).</p></sec></sec><sec id="Sec6"><title>Histone modification</title><p id="Par13">Histone modification can occur to the flexible tails as well as the core domain of histones, including those sites that are buried by DNA. In particular, the flexible histone tails are enriched with basic Lys/Arg and hydroxyl group-containing Ser/Thr/Tyr residues, thereby being hotspots for hallmark histone modifications. The tails extend from the surface of the nucleosome and are readily modulated by covalent posttranslational modification (PTM). PTMs modify histones by adding or removing chemical groups and regulate many biological processes via the activation or inactivation of genes. These processes mainly include acetylation and methylation of lysines (K) and arginines (R), phosphorylation of serines (S) and threonines (T), ubiquitylation, and sumoylation of lysines. In addition to those mentioned and discussed above, histone modifications also include citrullination, ADP-ribosylation, deamination, formylation, O-GlcNAcylation, propionylation, butyrylation, crotonylation, and proline isomerization at over 60 amino acid residues.<sup><xref ref-type="bibr" rid="CR157">157</xref>,<xref ref-type="bibr" rid="CR158">158</xref></sup> In addition to conventional PTMs, novel PTM sites are also found outside of the N-terminal tails.</p><p id="Par14">Histone modifications at certain sites, such as promoters and enhancers, are thought to be largely invariant, whereas a small number of these sites remain dynamic. H3K4me1 and H3K27ac, two dynamic modifications, were identified to activate enhancers and regulate gene expression.<sup><xref ref-type="bibr" rid="CR159">159</xref></sup> H3K9ac and H3K9me3 are two common modifications at promoters.<sup><xref ref-type="bibr" rid="CR160">160</xref>,<xref ref-type="bibr" rid="CR161">161</xref></sup> Appropriate histone modifications are important in gene expression and human biology; otherwise, alterations in PTMs may be associated with tumorigenesis. Analysis of cancer cells reveals that they exhibit aberrant histone modifications at individual genes or globally at the single-nuclei level.<sup><xref ref-type="bibr" rid="CR6">6</xref>,<xref ref-type="bibr" rid="CR162">162</xref></sup> Understanding histone modification patterns in cancer cells can help us to predict and treat cancers. Thus far, most studies have focused on aberrant modifications within an individual site, such as H4K20me3 or H4K16ac, rather than enzymatic activity-associated abnormalities. Generally, alterations in histone modifications occur at an early stage and accumulate during tumorigenesis.<sup><xref ref-type="bibr" rid="CR163">163</xref></sup></p><sec id="Sec7"><title>Histone acetylation (lysine)</title><p id="Par15">Histone acetylation occurs at multiple lysine residues at the N-terminus via the catalysis of histone acetyltransferases (HATs), also named lysine acetyltransferases (KATs). Histone acetylation regulates the compaction state of chromatin via multiple mechanisms, such as neutralizing the basic charge at unmodified lysine residues, and is associated with active transcription, especially at gene promoters and enhancers and the gene body; it also facilitates the recruitment of coregulators and RNA polymerase complexes to the locus.<sup><xref ref-type="bibr" rid="CR157">157</xref>,<xref ref-type="bibr" rid="CR164">164</xref></sup> To date, HATs and histone deacetylases (HDACs) are the two of the best characterized groups of enzymes involved in histone PTMs. HATs transfer the acetyl groups from acetyl-CoA cofactors to lysine residues at histones, whereas the role of HDACs is the opposite, which makes histone acetylation a highly reversible process.</p><sec id="Sec8"><title>Histone acetyltransferases</title><p id="Par16">HATs are predominantly located in the nucleus, but multiple lines of evidence have shown lysine acetylation in the cytoplasm, and their acetylation is associated with key cellular events.<sup><xref ref-type="bibr" rid="CR165">165</xref></sup> In addition, lysine acetylation found outside histones reminds us of the role of HATs in nonhistone PTMs.<sup><xref ref-type="bibr" rid="CR166">166</xref></sup> The first HAT was identified in yeast, and was named HAT1,<sup><xref ref-type="bibr" rid="CR167">167</xref></sup> and was then isolated from tetrahymena as HAT A by Allis and coworkers.<sup><xref ref-type="bibr" rid="CR168">168</xref></sup> In humans, HATs can be roughly divided into three groups: general control nondepressible 5 (GCN5)-related N-acetyl transferase (GNAT) (based on the protein Gcn5 found in yeast; including GCN5 and PCAF), MYST (based on the protein MOZ; including MOZ, MOF, TIP60, and HBO1), and p300/cAMP-responsive element-binding protein (CBP).<sup><xref ref-type="bibr" rid="CR169">169</xref></sup> Other HATs, including nuclear receptors and transcription factors, such as SRC1, MGEA5, ATF-2, and CLOCK, also harbor the ability to acetylate histones. Notably, a number of acetyltransferases also perform protein acetylation outside histones, such as TFIIB, MCM3AP, ESCO, and ARD1.<sup><xref ref-type="bibr" rid="CR170">170</xref></sup> Knockout of CBP/p300 is lethal for early embryonic mouse models.<sup><xref ref-type="bibr" rid="CR171">171</xref>,<xref ref-type="bibr" rid="CR172">172</xref></sup> The acetyl group transfer strategies for each HAT subfamily are different. For the GCN5 and PCAF family, the protein crystal structure shows a conserved glutamate in the active site. Blockade of this amino leads to a significantly decreased acetylation function.<sup><xref ref-type="bibr" rid="CR173">173</xref>,<xref ref-type="bibr" rid="CR174">174</xref></sup> Similarly, there is also a conserved glutamate plus a cysteine residue located at active sites of MYST family proteins.<sup><xref ref-type="bibr" rid="CR175">175</xref></sup> Unlike the other two families, the p300/CBP HAT subfamily has two other potential conserved residues, a tyrosine and a tryptophan.<sup><xref ref-type="bibr" rid="CR176">176</xref></sup> Generally, their catalytic mechanisms of acetyl group transfer can be divided into two groups. The GNAT family depends on a sequential ordered mechanism, whereas the members of the MYST family use a so-called ping-pong (i.e., double displacement) catalytic mechanism, which means that the acetyl groups are first transferred to a cysteine residue and then transferred to a lysine residue.<sup><xref ref-type="bibr" rid="CR177">177</xref></sup> In addition to differences in the acetyl transfer mechanism, HAT subfamilies, even different proteins in the same family, also have remarkable diversity in targeting sites.</p><p id="Par17">Appropriate acetylation within cells is important since upregulation or downregulation of HATs is associated with tumorigenesis or poor prognosis.<sup><xref ref-type="bibr" rid="CR162">162</xref>,<xref ref-type="bibr" rid="CR178">178</xref></sup> Compared with solid tumors, the association between histone modifications and cancer has been widely investigated in hematological malignancies. Germline mutation of CBP results in Rubinstein-Taybi syndrome along with an increased predisposition to childhood malignancies. Meanwhile, loss of another family member, p300, has also been associated with hematological malignancies.<sup><xref ref-type="bibr" rid="CR179">179</xref>,<xref ref-type="bibr" rid="CR180">180</xref></sup> Therefore, both CBP and p300 seem to function as tumor suppressors. During cancer development, the expression of HAT genes can be disrupted by chromosomal translocations, although these are rare events. Generation of the fused protein CBP-MOZ is the result of the t(8,16)(p11,p13) translocation in AML.<sup><xref ref-type="bibr" rid="CR181">181</xref></sup> Translocation of t(10;16)(q22;p13) leads to the CBP-MORF chimera.<sup><xref ref-type="bibr" rid="CR182">182</xref></sup> Similarly, p300-MOZ, MLL-CBP, and MLL-p300 (MLL, mixed lineage leukemia) have also been identified in hematological malignancies.<sup><xref ref-type="bibr" rid="CR183">183</xref>–<xref ref-type="bibr" rid="CR185">185</xref></sup> Generally, chromosomal rearrangements involving CBP are more common than those involving p300. Researchers have also investigated solid tumors, which are less mutated. The expression of translocated P300 in laryngeal squamous cell carcinoma (LSCC) tissue is much higher than that in adjacent normal tissue and is associated with advanced stage and poor prognosis.<sup><xref ref-type="bibr" rid="CR178">178</xref></sup> Missense point mutations in p300 are found in colorectal adenocarcinoma, gastric adenocarcinoma and breast cancer with quite low incidences.<sup><xref ref-type="bibr" rid="CR186">186</xref>,<xref ref-type="bibr" rid="CR187">187</xref></sup> Rare inactivating mutations in CBP and PCAF have only been identified in cancer cell lines but not primary tumors.<sup><xref ref-type="bibr" rid="CR188">188</xref></sup> Based on these findings, we hypothesize that the differences between cell lines and primary tumors cannot be ignored. Amplified in breast cancer 1 (AIB1), also frequently called NCOA3 (nuclear receptor coactivator 3) or SRC3 (steroid receptor coactivator 3), is overexpressed in ~60% of human breast cancers, and increased levels of AIB1 are associated with tamoxifen resistance and decreased overall survival.<sup><xref ref-type="bibr" rid="CR189">189</xref></sup> Steroid receptor coactivator 1 (SRC1) is also associated with the chromosomal translocation t(2;2)(q35;p23), which results in <italic>PAX3–NCOA1</italic> gene fusion in rhabdomyosarcoma without a consistent genetic abnormality during embryonic development<sup><xref ref-type="bibr" rid="CR190">190</xref></sup> (Table <xref rid="Tab2" ref-type="table">2</xref>).<table-wrap id="Tab2"><label>Table 2</label><caption><p>Important enzymes or proteins that regulate histone acetylation in cancer.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Enzyme</th><th>Synonym</th><th>Role in cancer</th><th>Cancer type</th><th>Associated biological process (involved mechanism and molecules)</th></tr></thead><tbody><tr><td colspan="5"><italic>Histone acetylases: the writers</italic></td></tr><tr><td colspan="5"> HAT1</td></tr><tr><td> HAT1</td><td>/</td><td>Promoter</td><td>Pancreatic cancer, nasopharyngeal cancer, hepatocellular carcinoma, esophageal carcinoma<sup><xref ref-type="bibr" rid="CR227">227</xref>–<xref ref-type="bibr" rid="CR230">230</xref></sup></td><td>Promote cell apoptosis, proliferation, differentiation and cisplatin resistance, associated with poor prognosis and upregulates PD-L1</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Lung cancer, osteosarcoma<sup><xref ref-type="bibr" rid="CR231">231</xref>,<xref ref-type="bibr" rid="CR232">232</xref></sup></td><td>Restores Fas expression and induces cancer cell apoptosis (Ras-ERK1/2 signaling)</td></tr><tr><td colspan="5"> GANT</td></tr><tr><td> GCN5L2</td><td>GCN5</td><td>Promoter</td><td>Prostate cancer, breast cancer, non-small-cell lung cancer, colorectal cancer<sup><xref ref-type="bibr" rid="CR233">233</xref>–<xref ref-type="bibr" rid="CR235">235</xref></sup></td><td>Promotes cell proliferation, apoptosis, EMT, poor prognosis of patients, promotion of E2F1, cyclin D1, and cyclin E1 expression (PI3K/PTEN/Akt signaling, TGF-β/Smad signaling pathway)</td></tr><tr><td> PCAF</td><td>/</td><td>Suppressor</td><td>Colorectal cancer, gastric cancer, prostate cancer, breast cancer<sup><xref ref-type="bibr" rid="CR236">236</xref>–<xref ref-type="bibr" rid="CR238">238</xref></sup></td><td>Decreased PCAF is associated with 5-FU resistance, poor clinical outcome (PCAF-p16-CDK4 axis, p53, miR-17)</td></tr><tr><td colspan="5"> MYST</td></tr><tr><td> HTATIP</td><td>TIP60</td><td>Promoter</td><td>Liver cancer, prostate cancer<sup><xref ref-type="bibr" rid="CR239">239</xref>,<xref ref-type="bibr" rid="CR240">240</xref></sup></td><td>Promotes cancer cell EMT, metastasis, radioresistance</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Breast cancer, lung cancer, bladder cancer, colorectal cancer<sup><xref ref-type="bibr" rid="CR241">241</xref>–<xref ref-type="bibr" rid="CR243">243</xref></sup></td><td>Is associated with cell viability and invasion, and low Tip60 expression is correlated with poor overall survival and relapse-free survival</td></tr><tr><td> MYST1</td><td>MOF</td><td>Promoter</td><td>Prostate cancer<sup><xref ref-type="bibr" rid="CR244">244</xref></sup></td><td>MYST1 increases the resistance to therapeutic regimens and promotes aggressive tumor growth (androgen receptor and NF-κB)</td></tr><tr><td> MYST2</td><td>HBO1</td><td>Promoter</td><td>Ovarian cancer, bladder cancer, breast cancer, pancreatic cancer, leukemia<sup><xref ref-type="bibr" rid="CR245">245</xref>–<xref ref-type="bibr" rid="CR247">247</xref></sup></td><td>Promotes cell proliferation, enrichment of cancer stem-like cells, gemcitabine resistance (Wnt/β-catenin signaling)</td></tr><tr><td> MYST3</td><td>MOZ</td><td>Promoter</td><td>Colorectal cancer, breast cancer, leukemia<sup><xref ref-type="bibr" rid="CR248">248</xref>–<xref ref-type="bibr" rid="CR250">250</xref></sup></td><td>Promotes cell proliferation, activates ERα expression (multiple fusion proteins: MOZ-TIF2, MOZ-NCOA2 and MOZ-CBP)</td></tr><tr><td> MYST4</td><td>MORF</td><td>Promoter</td><td>Leukemia<sup><xref ref-type="bibr" rid="CR251">251</xref></sup></td><td>MORF-CREBBP fusion</td></tr><tr><td colspan="5"> p300/CBP</td></tr><tr><td> P300</td><td>EP300, KAT3B</td><td>Promoter</td><td>Laryngeal squamous cell carcinoma, leukemia, nasopharyngeal carcinoma, hepatocellular carcinoma, cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma, colorectal cancer, breast cancer, lung cancer, gastric cancer, prostate cancer, cervical cancer, pancreatic cancer<sup><xref ref-type="bibr" rid="CR252">252</xref>–<xref ref-type="bibr" rid="CR257">257</xref></sup></td><td>Promotes cell proliferation, migration, invasion, EMT, and malignant transformation, is associated with advanced clinical stage, poor recurrence-free survival and overall survival, enhances ERα expression and contributes to tamoxifen resistance, castration resistance, and gemcitabine sensitivity, (p21, p27, β-catenin, MLL-p300, MOZ-p300 fusion, Smad2 and Smad3 in the TGF-β signaling pathway, p300/YY1/miR-500a-5p/HDAC2 signaling axis)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Bladder cancer, colorectal cancer<sup><xref ref-type="bibr" rid="CR258">258</xref>,<xref ref-type="bibr" rid="CR259">259</xref></sup></td><td>Downregulation of P300 is associated with chemosensitivity to 5-FU treatment and doxorubicin resistance</td></tr><tr><td> CBP</td><td>CREBBP, KAT3A</td><td>Promoter</td><td>Lung cancer, leukemia, gastric cancer, ovarian cancer, prostate cancer, hepatocellular carcinoma<sup><xref ref-type="bibr" rid="CR256">256</xref>,<xref ref-type="bibr" rid="CR260">260</xref>–<xref ref-type="bibr" rid="CR262">262</xref></sup></td><td>Is associated with drug resistance, a highly tumorigenic, cancer stem-like phenotype and enhances the activity of estrogen receptor-beta (ER-β) (CXCL8, PI3K/Akt/β-catenin/CBP axis); KAT6A-CREBBP, MOZ-CBP, MORF-CREBBP, MLL-CBP fusions in leukemia</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Lung cancer, prostate cancer<sup><xref ref-type="bibr" rid="CR263">263</xref>,<xref ref-type="bibr" rid="CR264">264</xref></sup></td><td>Loss of CBP reduces transcription of cellular adhesion genes while driving tumorigenesis</td></tr><tr><td colspan="5"> SRC/p160</td></tr><tr><td> NCOA1</td><td>SRC1</td><td>Promoter</td><td>Prostate cancer, colon cancer, breast cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma<sup><xref ref-type="bibr" rid="CR265">265</xref>–<xref ref-type="bibr" rid="CR267">267</xref></sup></td><td>Promotes cell invasion, proliferation, metastasis, is associated with shorter overall survival and progression-free survival (M-CSF1, miR-4443, miR-105-1)</td></tr><tr><td> NCOA2</td><td>TIF2</td><td>Promoter</td><td>Prostate cancer, leukemia<sup><xref ref-type="bibr" rid="CR268">268</xref>,<xref ref-type="bibr" rid="CR269">269</xref></sup></td><td>Is associated with resistance to AR antagonism and bicalutamide; MOZ-TIF2 fusion in leukemia</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Colorectal cancer, liver cancer<sup><xref ref-type="bibr" rid="CR270">270</xref>,<xref ref-type="bibr" rid="CR271">271</xref></sup></td><td>TIF2 is able to impair protumorigenic phenotypes</td></tr><tr><td> NCOA3</td><td>AIB1, ACTR</td><td>Promoter</td><td>Ovarian cancer, breast cancer, bladder cancer, gastric cancer, lung cancer, prostate cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, colorectal cancer, pancreatic cancer<sup><xref ref-type="bibr" rid="CR272">272</xref>–<xref ref-type="bibr" rid="CR275">275</xref></sup></td><td>Promotes cell proliferation, EMT, metastasis, invasiveness and is correlated to higher estrogen receptor expression, poor PFS and OS and predicts resistance to chemoradiotherapy (AKT, E2F1, SNAI1, cyclin E, cdk2, p53, matrix metalloproteinase 2 (MMP2) and MMP9 expression); however, high AIB1 expression has been correlated to both a good response to adjuvant tamoxifen and tamoxifen resistance.</td></tr><tr><td colspan="5"> Others</td></tr><tr><td> ATF-2</td><td>CREB2, CREBP1</td><td>Promoter</td><td>Pancreatic cancer, lung cancer, renal cell carcinoma, leukemia<sup><xref ref-type="bibr" rid="CR276">276</xref>–<xref ref-type="bibr" rid="CR278">278</xref></sup></td><td>Promotes cell proliferation, EMT, gemcitabine sensitivity (JNK1/c-Jun and p38 MAPK/ATF-2 pathways, miR-451); however, the level of ATF-2 is a key determinant of the sensitivity to tamoxifen</td></tr><tr><td> TFIIIC</td><td>/</td><td>Promoter</td><td>Ovarian cancer<sup><xref ref-type="bibr" rid="CR279">279</xref></sup></td><td>TFIIIC is overexpressed in cancer tissues</td></tr><tr><td> TAF1</td><td>TAFII250</td><td>/</td><td>/</td><td>/</td></tr><tr><td> CLOCK</td><td>KIAA0334</td><td>Promoter</td><td>Ovarian cancer, breast cancer<sup><xref ref-type="bibr" rid="CR280">280</xref>,<xref ref-type="bibr" rid="CR281">281</xref></sup></td><td>Promotes cell proliferation, migration, and invasion, is associated with drug resistance (cisplatin)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Lung cancer<sup><xref ref-type="bibr" rid="CR282">282</xref></sup></td><td>Is associated with cancer progression and metastasis</td></tr><tr><td> CIITA</td><td>MHC2TA</td><td>Suppressor</td><td>Breast cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma<sup><xref ref-type="bibr" rid="CR283">283</xref>–<xref ref-type="bibr" rid="CR285">285</xref></sup></td><td>Regulates the expression of MHC II and HLA-DR induction</td></tr><tr><td> MGEA5</td><td>NCOAT</td><td>promoter</td><td>Laryngeal cancer<sup><xref ref-type="bibr" rid="CR286">286</xref></sup></td><td>Is associated with larger tumor size, nodal metastases, higher grade and tumor behavior (TGFBR3-MGEA5 fusion)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR287">287</xref></sup></td><td>MGEA5 transcript levels were significantly lower in grade II and III than in grade I tumors; associated with lymph node metastasis</td></tr><tr><td> CDY</td><td>/</td><td>/</td><td>/</td><td>/</td></tr><tr><td colspan="5"><italic>Acetyl-lysine binding protein: the readers</italic></td></tr><tr><td colspan="5"> BRD and extraterminal domain (BET) proteins family</td></tr><tr><td> BRD2-4, BRDt</td><td>/</td><td>Promoter</td><td>Breast cancer, prostate cancer, gastric tumors, lung cancer, ovarian carcinoma, pancreatic cancer, hematologic malignancy, Ewing sarcoma, glioblastoma, melanoma<sup><xref ref-type="bibr" rid="CR288">288</xref>–<xref ref-type="bibr" rid="CR291">291</xref></sup></td><td>Is associated with cell proliferation, self-renewal, metabolism, metastasis, and expression of immune checkpoint molecules (oncogenic AR and MYC signaling, AMIGO2-PTK7 axis, Jagged1/Notch1 signaling, IKK activity)</td></tr><tr><td colspan="5"><italic>Histone deacetylases (HDACs): the erasers</italic></td></tr><tr><td colspan="5"> HDAC Class I</td></tr><tr><td> HDAC1</td><td>/</td><td>Promoter</td><td>Thyroid cancer, lung cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, gallbladder cancer, prostate cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR292">292</xref>–<xref ref-type="bibr" rid="CR295">295</xref></sup></td><td>Promotes cell invasion, viability, apoptosis, EMT; is associated with chemotherapy response. (CXCL8, P53, p38 MAPK, miRNA-34a)</td></tr><tr><td> HDAC2</td><td>/</td><td>Promoter</td><td>Pancreatic cancer, colorectal cancer, lung cancer, squamous cell carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, renal carcinoma, ovarian cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR296">296</xref>–<xref ref-type="bibr" rid="CR300">300</xref></sup></td><td>Promotes cell proliferation, metastasis, invasion, clonal expansion and EMT (E-cadherin, p63, mTORC1, AKT, PELP1/HDAC2/miR-200, p300/YY1/miR-500a-5p/HDAC2 axis, Sp1/HDAC2/p27 axis)</td></tr><tr><td> HDAC3</td><td>/</td><td>Promoter</td><td>Colorectal cancer, pancreatic cancer, breast cancer, colorectal cancer, prostate cancer, esophageal cancer, lung cancer<sup><xref ref-type="bibr" rid="CR301">301</xref>–<xref ref-type="bibr" rid="CR304">304</xref></sup></td><td>Promotes cell proliferation and invasion, migration, chemosensitivity; increases PD-L1 expression (NF‑κB signaling)</td></tr><tr><td> HDAC8</td><td>/</td><td>Promoter</td><td>Cervical cancer, breast cancer, colon cancer<sup><xref ref-type="bibr" rid="CR305">305</xref>–<xref ref-type="bibr" rid="CR307">307</xref></sup></td><td>Promotes cell migration, affects cell morphology and promotes the cell cycle (p53, HDAC8/YY1 axis)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR308">308</xref></sup></td><td>HDAC8 suppresses EMT (HDAC8/FOXA1 signaling)</td></tr><tr><td colspan="5"> HDAC Class II</td></tr><tr><td> HDAC4</td><td>/</td><td>Promoter</td><td>Head and neck cancer, breast cancer, colorectal cancer, gastric cancer, ovarian cancer, prostate cancer<sup><xref ref-type="bibr" rid="CR309">309</xref>–<xref ref-type="bibr" rid="CR311">311</xref></sup></td><td>Promotes cell viability, drug resensitization (tamoxifen, platinum) (STAT1, p21, miR-10b)</td></tr><tr><td> HDAC5</td><td>/</td><td>Promoter</td><td>Breast cancer, colorectal cancer, lung cancer, prostate cancer<sup><xref ref-type="bibr" rid="CR312">312</xref>,<xref ref-type="bibr" rid="CR313">313</xref></sup></td><td>Promotes cell proliferation, invasion, migration and EMT; is associated with hormone therapy resistance (HDAC5-LSD1 axis, Survivin and miR-125a-5p, miR-589-5p)</td></tr><tr><td> HDAC6</td><td>/</td><td>Promoter</td><td>Cervical cancer, breast cancer, colorectal cancer, gastric cancer, lung cancer, prostate cancer, liver cancer, ovarian cancer<sup><xref ref-type="bibr" rid="CR314">314</xref>–<xref ref-type="bibr" rid="CR317">317</xref></sup></td><td>Promotes pluripotency of CSCs, cancer cell proliferation and migration (α-tubulin, heat shock protein (HSP) 90, the NF-κB/MMP2 pathway, JNK/c-Jun pathway, miR-22, miR-221)</td></tr><tr><td> HDAC7</td><td>/</td><td>Promoter</td><td>Breast cancer, colorectal cancer, prostate cancer, ovarian cancer<sup><xref ref-type="bibr" rid="CR318">318</xref>–<xref ref-type="bibr" rid="CR320">320</xref></sup></td><td>Is associated with cancer stem cell-specific functions, tumor growth and invasion, and therapy resistance (miR-489, miR-34a)</td></tr><tr><td> HDAC9</td><td>/</td><td>Promoter</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR321">321</xref></sup></td><td>Enhances invasive and angiogenic potential (miR-206)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Lung cancer<sup><xref ref-type="bibr" rid="CR322">322</xref></sup></td><td>HDAC9 is downregulated in adenocarcinomas; is associated with tumor growth ability</td></tr><tr><td> HDAC10</td><td>/</td><td>Promoter</td><td>Ovarian cancer, lung cancer<sup><xref ref-type="bibr" rid="CR323">323</xref>,<xref ref-type="bibr" rid="CR324">324</xref></sup></td><td>Promotes cells proliferation, reduced DNA repair capacity and sensitization to platinum therapy (AKT phosphorylation)</td></tr><tr><td colspan="5"> HDAC Class III: sir2-like proteins (sirtuins)</td></tr><tr><td> Sirt1</td><td>/</td><td>Promoter</td><td>Breast cancer, colorectal cancer, prostate cancer, liver cancer, lung cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer<sup><xref ref-type="bibr" rid="CR325">325</xref>–<xref ref-type="bibr" rid="CR327">327</xref></sup></td><td>Promotes cell proliferation, migration, metastasis, EMT, metabolic flexibility and self-renewal of cancer stem cells, chemoresistance (miR-30a, miR-15b-5p)</td></tr><tr><td> Sirt2</td><td>/</td><td>promoter</td><td>Colorectal cancer lung cancer, renal cell carcinoma, gastric cancer, cervical cancer<sup><xref ref-type="bibr" rid="CR328">328</xref>–<xref ref-type="bibr" rid="CR330">330</xref></sup></td><td>Highly expressed in stem-like cells and promotes migration, invasion and metastasis (p53, RAS/ERK/JNK/MMP-9 pathway)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Breast cancer, prostate cancer lung cancer<sup><xref ref-type="bibr" rid="CR331">331</xref>-<xref ref-type="bibr" rid="CR333">333</xref></sup></td><td>Sensitizes cancer cells to intracellular DNA damage and the cell death induced by oxidative stress, and low Sirt2 levels were associated with poor patient survival (p27)</td></tr><tr><td> Sirt3</td><td>/</td><td>Promoter</td><td>Cervical cancer, lung cancer<sup><xref ref-type="bibr" rid="CR334">334</xref>,<xref ref-type="bibr" rid="CR335">335</xref></sup></td><td>Is associated with PD-L1-induced lymph node metastasis (p53)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Pancreatic cancer, breast cancer, prostate cancer, gastric cancer, ovarian cancer<sup><xref ref-type="bibr" rid="CR336">336</xref>–<xref ref-type="bibr" rid="CR338">338</xref></sup></td><td>Loss of SIRT3 leads to reactive oxygen species (ROS) generation that amplifies HIF-α stabilization; metastasis (<italic>c-MYC</italic>, CagA, PI3K/Akt pathway, Wnt/β-catenin pathway, AMP-activated protein kinase (AMPK))</td></tr><tr><td> Sirt4</td><td>/</td><td>Suppressor</td><td>Pancreatic cancer, thyroid cancer, gastric cancer, colorectal cancer<sup><xref ref-type="bibr" rid="CR339">339</xref>,<xref ref-type="bibr" rid="CR340">340</xref></sup></td><td>Promotes cell proliferation, aerobic glycolysis, migration and invasion, and in inhibition of glutamine metabolism (E-cadherin)</td></tr><tr><td> Sirt5</td><td>/</td><td>Promoter</td><td>Colorectal cancer, lung cancer, breast cancer<sup><xref ref-type="bibr" rid="CR341">341</xref>–<xref ref-type="bibr" rid="CR343">343</xref></sup></td><td>Promotes autophagy, cell proliferation, and drug resistance, and is associated with poor clinical outcomes</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Liver cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR344">344</xref>,<xref ref-type="bibr" rid="CR345">345</xref></sup></td><td>Inhibits peroxisome-induced oxidative stress (CDK2)</td></tr><tr><td> Sirt6</td><td>/</td><td>Promoter</td><td>Pancreatic cancer, lung cancer, prostate cancer<sup><xref ref-type="bibr" rid="CR346">346</xref>–<xref ref-type="bibr" rid="CR348">348</xref></sup></td><td>Enhances cytokine production, and promotes EMT, cell migration and tumor metastasis, and predicts poor prognosis (ERK1/2/MMP9 pathway, SIRT6/Snail/KLF4 axis)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Pancreatic cancer, breast cancer, liver cancer<sup><xref ref-type="bibr" rid="CR349">349</xref>,<xref ref-type="bibr" rid="CR350">350</xref></sup></td><td>Promotes increased glycolysis, cancer cell proliferation and tumor growth, and is associated with paclitaxel, epirubicin, and trastuzumab sensitivity (survivin, NF-κB pathway)</td></tr><tr><td> Sirt7</td><td>/</td><td>Promoter</td><td>Colorectal cancer, gastric cancer, bladder cancer<sup><xref ref-type="bibr" rid="CR351">351</xref>,<xref ref-type="bibr" rid="CR352">352</xref></sup></td><td>Accelerates cell growth, proliferation, motility and apoptosis (MAPK pathway)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Pancreatic cancer, breast cancer, lung cancer, colorectal cancer<sup><xref ref-type="bibr" rid="CR353">353</xref>–<xref ref-type="bibr" rid="CR355">355</xref></sup></td><td>Sensitizes to gemcitabine and radiotherapy, and low levels of SIRT7 are associated with an aggressive tumor phenotype and poor outcome (TGF-β signaling, p38 MAPK)</td></tr><tr><td colspan="5"> HDAC Class IV</td></tr><tr><td> HDAC11</td><td>/</td><td>Promoter</td><td>Liver cancer, Hodgkin lymphoma, neuroblastoma, colorectal cancer, prostate cancer, breast cancer, ovarian cancer<sup><xref ref-type="bibr" rid="CR356">356</xref>–<xref ref-type="bibr" rid="CR359">359</xref></sup></td><td>Promotes the mitotic cell cycle, cell apoptosis; is associated with cancer progression and survival (OX40 ligand, p53)</td></tr></tbody></table><table-wrap-foot><p><italic>EMT</italic> epithelial-mesenchymal transition, <italic>PI3K</italic> phosphatidylinositol 3-kinase, <italic>TGF-β</italic> transforming growth factor β, <italic>ER</italic> estrogen receptor, <italic>CSF</italic> colony-stimulating factor, <italic>AR</italic> androgen receptor, <italic>MMP</italic> matrix metalloproteinase</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec9"><title>Acetyl-lysine recognition proteins</title><p id="Par18">The bromodomain (BRD) motif is an ~110-amino-acid conserved protein module and is regarded as the first and sole histone-binding module that contains a hydrophobic pocket to identify acetyl-lysine.<sup><xref ref-type="bibr" rid="CR191">191</xref></sup> The specificity of different BRDs depends on the sequences within the loops that form the hydrophobic pocket. Therefore, each BRD has a preference for different histones.<sup><xref ref-type="bibr" rid="CR192">192</xref>,<xref ref-type="bibr" rid="CR193">193</xref></sup> In addition to their recognition of acetyl-lysine, BRDs are also capable of interacting with other chromatin molecules, such as plant homeodomain (PHD) finger motifs or another BRD. To date, 42 proteins containing bromodomains and 61 unique bromodomains have been discovered.<sup><xref ref-type="bibr" rid="CR194">194</xref>,<xref ref-type="bibr" rid="CR195">195</xref></sup> Based on the sequence length and sequence identity of BRDs, the human BRD family can be divided into nine groups and one additional set of outliers, which has been well illustrated in published papers.<sup><xref ref-type="bibr" rid="CR169">169</xref>,<xref ref-type="bibr" rid="CR194">194</xref></sup> Different BRD-containing proteins contain one to six BRDs. Intriguing, the most notable and well-studied bromodomain proteins are also HATs, such as PCAF, GCN5, and p300/CBP. Yaf9, ENL, AF9, Taf14, Sas5 (YEATS), and double PHD finger (DPF) have also been discovered to be acyl-lysine reader domains.<sup><xref ref-type="bibr" rid="CR191">191</xref>,<xref ref-type="bibr" rid="CR196">196</xref></sup> Human MOZ and DPF2 are two proteins containing the DPF domain. Mutations in the YEATS and DPF domains are associated with cancer. For example, mutation of AF9 has been found in hematological malignancies, and ENL dysregulation leads to kidney cancer.<sup><xref ref-type="bibr" rid="CR197">197</xref>,<xref ref-type="bibr" rid="CR198">198</xref></sup></p><p id="Par19">Another important family is the BRD and extraterminal domain (BET) protein family, including BRD2, BRD3, BRD4, and BRDt, and this family shares two conserved N-terminal bromodomains and a more divergent C-terminal recruitment domain.<sup><xref ref-type="bibr" rid="CR199">199</xref>,<xref ref-type="bibr" rid="CR200">200</xref></sup> These bromodomain proteins are critical as mediators of gene transcriptional activity.<sup><xref ref-type="bibr" rid="CR201">201</xref></sup> Of note, bromodomains have also been found in some histone lysine methyltransferases, such as ASH1L and MLL. BRDs are promiscuous domains and have been discussed in other well-constructed papers.<sup><xref ref-type="bibr" rid="CR169">169</xref>,<xref ref-type="bibr" rid="CR194">194</xref></sup> In this review, we focus on the role of BRDs in tumorigenesis.</p><p id="Par20">As histone acetylation “readers”, bromodomain proteins play important roles in tumorigenesis. BRD4 recruits the positive transcription elongation factor complex (P-TEFb), a validated target in chronic lymphocytic leukemia associated with <italic>c-Myc</italic> activity.<sup><xref ref-type="bibr" rid="CR202">202</xref>–<xref ref-type="bibr" rid="CR204">204</xref></sup> Chromosomal translocation of BRD4, via the t(15;19) translocation, results in the generation of the fusion protein BRD4-NUT (nuclear protein in testis), which is found in NUT midline carcinoma (NMC). Importantly, inhibition of BRD4-NUT induces differentiation of NMC cells.<sup><xref ref-type="bibr" rid="CR205">205</xref></sup> Moreover, BRD4 is required for the maintenance of AML with sustained expression of Myc<sup><xref ref-type="bibr" rid="CR206">206</xref></sup> (Table <xref rid="Tab2" ref-type="table">2</xref>).</p></sec><sec id="Sec10"><title>Histone deacetylases</title><p id="Par21">Histone deacetylases (HDACs) have recently attracted increasing attention. In humans, the genome encodes 18 HDACs. In contrast to the function of HATs, HDACs usually act as gene silencing mediators and repress transcription. Similarly, HDACs are expressed not only in the nucleus but also in the cytoplasm, and their substrates are also not limited to histones. Based on sequence similarity, HDACs can be divided into four classes: class I HDACs, yeast Rpd3-like proteins, are transcriptional corepressors and have a single deacetylase domain at the N-terminus and diversified C-terminal regions (HDAC1, HDAC2, HDAC3, and HDAC8); class II HDACs, yeast Hda1-like proteins, have a deacetylase domain at a C-terminal position (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10); class III HDACs are yeast silent information regulator 2 (Sir2)-like proteins (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7); and class IV involves one protein (HDAC11). The class IV protein shares sequence similarity with both class I and class II proteins.<sup><xref ref-type="bibr" rid="CR207">207</xref>,<xref ref-type="bibr" rid="CR208">208</xref></sup> Classes I, II, and IV are included in the histone deacetylase family, whereas class III HDACs belong to the Sir2 regulator family.<sup><xref ref-type="bibr" rid="CR209">209</xref></sup> The catalytic mechanisms for these two families are different; classes I, II, and IV are Zn<sup>2+</sup>-dependent HDACs, whereas sir2-like proteins (sirtuins) are nicotinamide adenine dinucleotide (NAD<sup>+</sup>)-dependent HDACs and are also capable of mono-ADP-ribosyltransferase activity, another pattern of histone modification.<sup><xref ref-type="bibr" rid="CR210">210</xref></sup> Intriguingly, SIRT4 is thought to have more mono-ADP-ribosyltransferase activity than HDAC activity. SIR2 and SIRT6 seem to have equal levels of both mono-ADP-ribosyltransferase and HDAC activities.<sup><xref ref-type="bibr" rid="CR211">211</xref>,<xref ref-type="bibr" rid="CR212">212</xref></sup> Moreover, after revealing the crystal structure of SIRT5, researchers found that SIRT5 is also a lysine desuccinylase and demalonylase.<sup><xref ref-type="bibr" rid="CR213">213</xref></sup> Therefore, the diversity of the sirtuin family makes them a group of multifunctional enzymes.</p><p id="Par22">So far, the major known recognition sites of each HDAC are different, and these largely remain to be uncovered. For example, HDAC3 is thought to deacetylate H4K8 and H4K12,<sup><xref ref-type="bibr" rid="CR214">214</xref></sup> but in an HDAC3-knockout HeLa cell line, the acetylation levels of H4K8 and H4K12, even the overall acetylation levels of H3 and H4, were comparable with those in wild-type cells.<sup><xref ref-type="bibr" rid="CR215">215</xref></sup> Nevertheless, HDAC1 or HDAC3 siRNA can indeed increase the acetylation levels of H3K9 and H3K18.<sup><xref ref-type="bibr" rid="CR215">215</xref></sup> Therefore, partially because of the functional complementation and diversity within HDAC families, especially in class I, II, and IV, it is difficult to identify the specific substrates of certain HDACs. However, the substrates of the sirtuin family are quite clear. It is notable that because SIRT4 and SIRT5 are only located in mitochondria, they have no effect on histones. However, nonhistone lysine acetylation is also prevalent, since more than 3600 acetylation sites on 1750 proteins have been identified.<sup><xref ref-type="bibr" rid="CR166">166</xref></sup> The tumor suppressor p53 and the cytoskeletal protein α-tubulin are two representative substrates of HDACs.<sup><xref ref-type="bibr" rid="CR216">216</xref>–<xref ref-type="bibr" rid="CR218">218</xref></sup> Notably, HDACs are also capable of regulating gene transcription by deacetylating other proteins that are responsible for epigenetic events, such as DNMTs, HATs, and HDACs.<sup><xref ref-type="bibr" rid="CR166">166</xref>,<xref ref-type="bibr" rid="CR219">219</xref></sup> Another phenomenon is that some HDACs have to form a complex along with other components to function as transcriptional corepressors, which provides ideas and methods to design novel HDAC inhibitors. The Sin3, NuRD, and CoREST complexes are three complexes containing HDAC1 and HDAC2. Studies have found that purified HDAC1 or HDAC2 without associated components shows fairly weak deacetylation activity in vitro.<sup><xref ref-type="bibr" rid="CR220">220</xref></sup> HDAC3 interacts with the corepressors SMRT/NCoR to form the functional complexes, which significantly increases HDAC3 activity. NCoR also interacts with HDAC1, HDAC2 and the class II deacetylases HDAC4, HDAC5, and HDAC7, but usually not in the form of a complex.<sup><xref ref-type="bibr" rid="CR221">221</xref>,<xref ref-type="bibr" rid="CR222">222</xref></sup> Deleted in breast cancer 1 (DBC1) and active regulator of SIRT1 (AROS) are two proteins that are able to bind to SIRT1, whereas their interactions present opposite functions. The DBC1/SIRT1 complex inhibits the deacetylation activity of SIRT1, whereas the combination of AROS and SIRT1 stimulates the activity of SIRT1.<sup><xref ref-type="bibr" rid="CR223">223</xref>,<xref ref-type="bibr" rid="CR224">224</xref></sup></p><p id="Par23">HDACs not only are able to deacetylate histones and nonhistone proteins but also interact with other epigenetic-associated enzymes, which gives them a vital role in tumorigenesis.<sup><xref ref-type="bibr" rid="CR162">162</xref>,<xref ref-type="bibr" rid="CR178">178</xref></sup> Alterations in HDACs in cancers usually result in aberrant deacetylation and inactivation of tumor suppressor genes. For example, hypoacetylation of the promoter of p21, a tumor suppressor encoded by <italic>CDKN1A</italic>, can be reversed by HDAC inhibitors, resulting in an antitumor effect.<sup><xref ref-type="bibr" rid="CR225">225</xref></sup> A screen of the mutations in several HATs and HDACs, such as CBP, PCAF, HDAC1, HDAC2, HDAC5, HDAC7, and SIRT1, in more than 180 cancer samples including primary tumors and cancer cells indicated that the expression profiles of HDAC1, HDAC5, HDAC7, and SIRT1 are distinctive for colorectal cancers and normal colorectal mucosa, and the expression profiles of HDAC4 and CBP are capable of distinguishing breast cancer tissue from normal tissues<sup><xref ref-type="bibr" rid="CR226">226</xref></sup> (Table <xref rid="Tab2" ref-type="table">2</xref>).</p></sec></sec><sec id="Sec11"><title>Histone methylation (lysine and arginine)</title><p id="Par24">Similar to the process of histone acetylation, histone methylation also consists of three important components: “writers”, histone methyltransferases (HMTs), “readers”, histone methylation-recognizing proteins, and “erasers”, histone demethylases (HDMs). Methylation of histones occurs at arginine and lysine residues. Arginine and lysine both can be monomethylated or dimethylated, whereas lysine is also capable of being trimethylated. Histone methylation can either promote or inhibit gene expression, which depends on the specific situation. For example, lysine methylation at H3K9, H3K27, and H4K20 is generally associated with suppression of gene expression, whereas methylation of H3K4, H3K36, and H3K79 induces gene expression.<sup><xref ref-type="bibr" rid="CR360">360</xref></sup> Mutation of H3K27M (lysine 27 to methionine) and H3K36M are two important oncogenic events, and H3K27M and H3K36M serve as drivers of pediatric gliomas and sarcomas. H3K27M has been identified in more than 70% of diffuse intrinsic pontine gliomas (DIPGs) and 20% of pediatric glioblastomas, which results in a global reduction in the trimethylation of H3K27 (H3K27me3).<sup><xref ref-type="bibr" rid="CR361">361</xref>–<xref ref-type="bibr" rid="CR363">363</xref></sup> However, the H3K36M mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma, leading to increased levels of H3K27me3 and global loss of H3K36 (me2 and me).<sup><xref ref-type="bibr" rid="CR364">364</xref>,<xref ref-type="bibr" rid="CR365">365</xref></sup> Meanwhile, depletion of H3K36 methyltransferases results in similar phenotypes to those seen with H3K36M mutation.<sup><xref ref-type="bibr" rid="CR364">364</xref></sup> To date, KMTs (lysine methyltransferases) have been better studied than arginine methyltransferases (PRMTs) due to their sequence of discovery, different prevalence and impact. Their targets are not limited to only histones, they also modify other key proteins, such as the tumor suppressor p53, TAF10, and Piwi proteins.<sup><xref ref-type="bibr" rid="CR366">366</xref>–<xref ref-type="bibr" rid="CR368">368</xref></sup></p><sec id="Sec12"><title>Histone methyltransferases</title><p id="Par25">All KMTs contain a 130-amino-acid conserved domain, the SET (suppressor of variegation, enhancer of Zeste, trithorax) domain, except for DOT1L. The SET domain is responsible for the enzymatic activity of SET-containing KMTs. Instead of methylating lysine residues in histone tails, DOT1L methylates lysine in the globular core of the histone, and its catalytic domain is more similar to that of PRMTs.<sup><xref ref-type="bibr" rid="CR369">369</xref>,<xref ref-type="bibr" rid="CR370">370</xref></sup> The enzymatic activity of KMTs results in the transfer of a methyl group from S-adenosylmethionine (SAM) to a the ε-amino group of a lysine residue. The first identified KMT was SUV39H1, which targets H3K9.<sup><xref ref-type="bibr" rid="CR371">371</xref></sup> Sequentially, more than 50 SET-containing proteins have been identified with proven or predicted lysine methylation potential. Of note, KMTs are highly specific enzymes, meaning that they are highly selective for lysine residues they can methylate and the specific methylation degree they can achieve. For example, SUV39H1 and SUV39H2 specifically methylate histone 3 at lysine 9 (H3K9), and DOT1L only methylates H3K79.<sup><xref ref-type="bibr" rid="CR371">371</xref></sup> Based on their structure and sequence around the SET domain, generally, KMTs can be divided into six groups, SUV39, SET1, SET2, EZH, SMYD, and RIZ (PRDM) (reviewed by Volkel and Angrand<sup><xref ref-type="bibr" rid="CR372">372</xref></sup>). The Pre-SET domain of the SUV39 family contains nine conserved cysteines that coordinate with three zinc ions to function. The SET1 family members share a similar Post-SET motif that contains three conserved cysteine residues. The SET2 family possesses an AWS motif that contains 7–9 cysteines. Their SET domain is located between the AWS motif and a Post-SET motif. The members of the enhancer of zeste homolog (EZH) family are the catalytic components of polycomb repressive complexes (PRCs), which are responsible for gene silencing. EZH proteins have no Post-SET motif but have 15 cysteines in front of the SET domain and show no methylated activity as isolated proteins.<sup><xref ref-type="bibr" rid="CR373">373</xref></sup> PRC2 shows lysine methylation activity through its catalytic components, EZH2 or its homolog EZH1.<sup><xref ref-type="bibr" rid="CR374">374</xref></sup> EZH2 can methylate not only histone H3 but also histone H1 at lysine 26.<sup><xref ref-type="bibr" rid="CR375">375</xref></sup> The SMYD family members, which are SET and MYND domain-containing proteins, possesses a MYND (myeloid-nervy-DEAF1) domain, a zinc-finger motif responsible for protein–protein interaction.<sup><xref ref-type="bibr" rid="CR376">376</xref></sup> The RIZ (PRDM) family is a large family containing a homolog of the SET domain, the PR domain. The PR and SET domains share 20–30% sequence identity and are both capable of inducing histone H3 methylation.<sup><xref ref-type="bibr" rid="CR377">377</xref></sup> However, most members of the RIZ family responsible for histone methylation are still unknown. So far, two of them have been proven to induce the methylation of histones: PRDM2 (RIZ1) is associated with H3K9 methylation; and Meisetz, the mouse homolog of PRDM9, trimethylates H3K4.<sup><xref ref-type="bibr" rid="CR378">378</xref></sup> Meanwhile, PRDM1 has been identified to interact with EHMT2, a member of the SUV39 family. PRDM6 acts as a transcription suppressor by interacting with class I HDACs and EHMT2 to induce cell proliferation and inhibit cell differentiation.<sup><xref ref-type="bibr" rid="CR379">379</xref></sup> Meanwhile, the recruitment of EHMT2 is based on the formation of a complex with PRDM1.<sup><xref ref-type="bibr" rid="CR380">380</xref></sup> Due to the lack of a characteristic sequence or structure flanking the SET domain, other SET-containing KMTs, such as SET7/9, SET8, SUV4-20H1, and SUV4-20H2, cannot be classified into these families. Notably, some KMTs contain more than one domain, which allows them to interact with other proteins, especially other epigenetic modifying proteins. SUV39H1 possesses a chromodomain that directly binds to nucleic acids and forms heterochromatin.<sup><xref ref-type="bibr" rid="CR381">381</xref></sup> MLL1 recognizes unmethylated DNA through its CpG-interacting CXXC domain. SETDB1 contains an MBD that interacts with methylated DNA.<sup><xref ref-type="bibr" rid="CR382">382</xref></sup> The Tudor domain in SETDB1 may potentially recognize the methylation of lysine residues.<sup><xref ref-type="bibr" rid="CR383">383</xref></sup> ASH1 is able to interact with CBP, a HAT, via a bromodomain within ADH1.<sup><xref ref-type="bibr" rid="CR384">384</xref></sup></p><p id="Par26">Protein arginine methyltransferases (PRMTs) can be divided into two groups. Among the nine PRMTs, only PRMT5, PRMT7, and PRMT9 are type II PRMTs, and the other five PRMTs, except for PRMT2, are type I PRMTs. PRMT2 was identified by sequence homology<sup><xref ref-type="bibr" rid="CR385">385</xref></sup> but has not shown any catalytic activity during investigations, although PRMT2 acts as a strong coactivator for androgen receptor (AR), which is thought to be associated with arginine methylation.<sup><xref ref-type="bibr" rid="CR386">386</xref></sup> Both types of PRMTs first catalyze the formation of monomethylarginine as an intermediate. However, sequentially, type I PRMTs can form asymmetric dimethylarginine (ADMA, Rme2a), but type II PRMTs form symmetric dimethylarginine (SDMA, Rme2s). Rme2a means two methyl groups on one ω-amino group, whereas an Rme2s has one methyl group on each ω-amino group. PRMT1-PRMT8 were investigated by Herrmann and Fackelmayer,<sup><xref ref-type="bibr" rid="CR387">387</xref></sup> and FBXO11 was identified as PRMT9, which symmetrically dimethylates arginine residues.<sup><xref ref-type="bibr" rid="CR388">388</xref></sup></p><p id="Par27">Most enzymes for histone methylation are substrate-specific proteins; therefore, alterations in the aberrant expression of enzymes are usually associated with specific histone residue mutations. One of the best-known examples of alterations in tumorigenesis is H3K4me3, which is associated with biphenotypic (mixed lineage) leukemia (MLL). The location of the MLL gene is where chromosomal translocations in AML and ALL usually occur.<sup><xref ref-type="bibr" rid="CR389">389</xref></sup> When the MLL gene is translocated, the catalytic SET domain is lost, which results in MLL translocation-generated fusion proteins, which recruit DOT1L.<sup><xref ref-type="bibr" rid="CR390">390</xref></sup> Maintenance of MLL-associated ALL depends on the methylation of H3K79 catalyzed by DOT1L.<sup><xref ref-type="bibr" rid="CR391">391</xref></sup> Therefore, DOT1L is usually associated with hematological malignancies rather than solid tumors. Alteration of the EZH2-induced methylation of H3K27 has been observed in multiple cancers, including various solid tumors (prostate, breast, kidney, bladder, and lung cancers) and hematological malignancies.<sup><xref ref-type="bibr" rid="CR392">392</xref></sup> Meanwhile, overexpression of EZH2 has been found in multiple cancers and is associated with poor prognosis.<sup><xref ref-type="bibr" rid="CR393">393</xref></sup> Different mechanisms have been proposed to describe the role of EZH2 in tumorigenesis (Table <xref rid="Tab3" ref-type="table">3</xref>).<table-wrap id="Tab3"><label>Table 3</label><caption><p>Important enzymes or proteins that regulate histone methylation in cancer.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Enzymes</th><th>Synonyms</th><th>Role in cancer</th><th>Cancer type</th><th>Mechanism</th></tr></thead><tbody><tr><td colspan="5"><italic>Histone methyltransferases (lysine): the writers for lysine</italic></td></tr><tr><td colspan="5">SUV39</td></tr><tr><td> KMT1A</td><td>SUV39H1, MG44, SUV39H</td><td>Promoter</td><td>Gastric cancer, prostate cancer, breast cancer, lung cancer, colorectal cancer, bladder cancer<sup><xref ref-type="bibr" rid="CR421">421</xref>–<xref ref-type="bibr" rid="CR426">426</xref></sup></td><td>Promotes cell migration and cancer stem cell self-renewal (KMT1A-GATA3-STAT3 axis)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Breast cancer, cervical cancer<sup><xref ref-type="bibr" rid="CR427">427</xref>,<xref ref-type="bibr" rid="CR428">428</xref></sup></td><td>SUV39H1-low tumors are correlated with poor clinical outcomes</td></tr><tr><td> KMT1B</td><td>FLJ23414, SUV39H2</td><td>Promoter</td><td>Colorectal cancer, lung cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR429">429</xref>–<xref ref-type="bibr" rid="CR431">431</xref></sup></td><td>Promotes cell proliferation, migration and invasion and tumor metastasis</td></tr><tr><td> KMT1C</td><td>EHMT2, G9A, BAT8, NG36</td><td>Promoter</td><td>Breast cancer, pancreatic cancer, bladder cancer, ovarian cancer, liver cancer, colon cancer, lung cancer<sup><xref ref-type="bibr" rid="CR432">432</xref>–<xref ref-type="bibr" rid="CR435">435</xref></sup></td><td>Promotes cell proliferation, metastasis, and apoptosis, and is associated with poor prognosis (p27, PMAIP1-USP9X-MCL1 axis, Wnt signaling pathway)</td></tr><tr><td> KMT1E</td><td>SETDB1, ESET, KG1T</td><td>Promoter</td><td>Breast cancer, colorectal cancer, hepatocellular carcinoma, liver cancer<sup><xref ref-type="bibr" rid="CR436">436</xref>–<xref ref-type="bibr" rid="CR439">439</xref></sup></td><td>SETDB1 promotes cell proliferation, migration, invasion, and EMT (p53)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Lung cancer<sup><xref ref-type="bibr" rid="CR440">440</xref></sup></td><td>SETDB1 acts as a metastasis suppressor, and inhibits cell migration and invasive behavior.</td></tr><tr><td colspan="5">SET1</td></tr><tr><td> KMT2A</td><td>MLL1, HRX, TRX1, ALL-1</td><td>Promoter</td><td>Head and neck cancer, pancreatic cancer, prostate cancer<sup><xref ref-type="bibr" rid="CR441">441</xref>,<xref ref-type="bibr" rid="CR442">442</xref></sup></td><td>Promotes PD-L1 transcription and is associated with the self-renewal of cancer cells (Wnt/β-catenin pathway)</td></tr><tr><td> KMT2B</td><td>ALR, MLL2</td><td>promoter</td><td>Bladder cancer, lung cancer, breast cancer<sup><xref ref-type="bibr" rid="CR443">443</xref>–<xref ref-type="bibr" rid="CR445">445</xref></sup></td><td>Is associated with the self-renewal of CSCs and expansion (Wnt/β-catenin pathway)</td></tr><tr><td> KMT2C</td><td>MLL3, HALR</td><td>Suppressor</td><td>Colorectal cancer, esophageal squamous cell carcinoma<sup><xref ref-type="bibr" rid="CR446">446</xref></sup></td><td>Inhibits tumor growth and metastasis</td></tr><tr><td> KMT2D</td><td>MLL4, HRX2</td><td>Promoter</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR447">447</xref></sup></td><td>Promotes cell proliferation and invasiveness</td></tr><tr><td> KMT2E</td><td>MLL5</td><td>Promoter</td><td>Glioblastoma<sup><xref ref-type="bibr" rid="CR448">448</xref></sup></td><td>Is associated with cancer cell self-renewal</td></tr><tr><td> KMT2F</td><td>SET1A</td><td>Promoter</td><td>Liver cancer<sup><xref ref-type="bibr" rid="CR449">449</xref></sup></td><td>Promotes liver cancer growth and hepatocyte-like stem cell malignant transformation</td></tr><tr><td colspan="5">EZH</td></tr><tr><td> EZH1</td><td>KIAA0388</td><td>Promoter</td><td>Breast cancer, prostate cancer, bladder cancer, colorectal cancer, liver cancer, gastric cancer, melanoma, lymphoma, myeloma, Ewing’s sarcoma, glioblastoma, thyroid carcinoma, esophageal squamous cell carcinoma, lung cancer, ovarian cancer, renal cancer<sup><xref ref-type="bibr" rid="CR392">392</xref>,<xref ref-type="bibr" rid="CR450">450</xref>–<xref ref-type="bibr" rid="CR452">452</xref></sup></td><td>Promotes cell proliferation, colony formation, migration and tumor metastasis; is associated with cancer stem cell maintenance; predicts chemotherapeutic efficacy and response to tamoxifen therapy (E-cadherin, RUNX3, MEK-ERK1/2-Elk-1 pathway)</td></tr><tr><td> EZH2</td><td>KMT6, ENX-1, MGC9169</td><td></td><td></td><td></td></tr><tr><td colspan="5">SET2</td></tr><tr><td> KMT3A</td><td>SETD2, SET2, HIF-1,</td><td>Suppressor</td><td>Renal cancer, lung cancer<sup><xref ref-type="bibr" rid="CR453">453</xref>,<xref ref-type="bibr" rid="CR454">454</xref></sup></td><td>Maintains genome integrity and attenuates cisplatin resistance (ERK signaling pathway)</td></tr><tr><td> WHSC1</td><td>NSD2, WHS, TRX5</td><td>Promoter</td><td>Prostate cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR455">455</xref>,<xref ref-type="bibr" rid="CR456">456</xref></sup></td><td>Promotes cell invasive properties, EMT and cancer metastasis</td></tr><tr><td> WHSC1L1</td><td>NSD3, MGC126766</td><td>Promoter</td><td>Breast cancer, head and neck cancer<sup><xref ref-type="bibr" rid="CR457">457</xref></sup></td><td>Is associated with ERα overexpression and enhances the oncogenic activity of EGFR</td></tr><tr><td colspan="5">RIZ (PRDM)</td></tr><tr><td> PRDM1</td><td>BLIMP1</td><td>Promoter</td><td>Pancreatic cancer, breast cancer<sup><xref ref-type="bibr" rid="CR458">458</xref>,<xref ref-type="bibr" rid="CR459">459</xref></sup></td><td>Promotes cell invasiveness and cancer metastasis</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Lung cancer, colon cancer<sup><xref ref-type="bibr" rid="CR460">460</xref>,<xref ref-type="bibr" rid="CR461">461</xref></sup></td><td>Inhibits cell invasion and metastasis (p21)</td></tr><tr><td> PRDM2</td><td>RIZ</td><td>Promoter</td><td>Colorectal cancer, breast cancer<sup><xref ref-type="bibr" rid="CR462">462</xref>,<xref ref-type="bibr" rid="CR463">463</xref></sup></td><td>Is associated with poor clinicopathological variables and mediates the proliferative effect of estrogen</td></tr><tr><td> PRDM3</td><td>EVI1, MDS1-EVI1</td><td>Promoter</td><td>Ovarian cancer, nasopharyngeal carcinoma<sup><xref ref-type="bibr" rid="CR464">464</xref>,<xref ref-type="bibr" rid="CR465">465</xref></sup></td><td>Promotes cell proliferation, migration, EMT, cancer stem cells and chemoresistance/radioresistance</td></tr><tr><td> PRDM4</td><td>PFM1</td><td>Promoter</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR466">466</xref></sup></td><td>Is associated with cancer cell stemness, tumorigenicity, and tumor metastasis</td></tr><tr><td> PRDM5</td><td>PFM2</td><td>Suppressor</td><td>Colorectal cancer, gastric cancer, cervical cancer<sup><xref ref-type="bibr" rid="CR467">467</xref></sup></td><td>Among the PRDM family genes tested, PRDM5 was the most frequently silenced in colorectal and gastric cancer</td></tr><tr><td> PRDM9</td><td>PFM6</td><td>Promoter</td><td>N/A<sup><xref ref-type="bibr" rid="CR468">468</xref></sup></td><td>Impairs genomic instability and drives tumorigenesis</td></tr><tr><td> PRDM14</td><td>PFM11</td><td>Promoter</td><td>Testicular cancer, pancreatic cancer<sup><xref ref-type="bibr" rid="CR469">469</xref>,<xref ref-type="bibr" rid="CR470">470</xref></sup></td><td>Is associated with early germ cell specification and promotes cancer stem-like properties and liver metastasis</td></tr><tr><td> PRDM16</td><td>MEL1, PFM13</td><td>promoter</td><td>Gastric cancer<sup><xref ref-type="bibr" rid="CR471">471</xref></sup></td><td>Inhibits TGF-beta signaling by stabilizing the inactive Smad3-SKI complex</td></tr><tr><td colspan="5">SMYD</td></tr><tr><td> KMT3C</td><td>SMYD2</td><td>Promoter</td><td>Pancreatic cancer, gastric cancer, breast cancer, lung cancer<sup><xref ref-type="bibr" rid="CR472">472</xref>,<xref ref-type="bibr" rid="CR473">473</xref></sup></td><td>Promotes cancer cell proliferation and survival (STAT3, EML4-ALK, p65)</td></tr><tr><td> KMT3E</td><td>SMYD3, ZMYND1, ZNFN3A1, FLJ21080</td><td>Promoter</td><td>Liver and colon cancer, prostate cancer, breast cancer<sup><xref ref-type="bibr" rid="CR474">474</xref>–<xref ref-type="bibr" rid="CR476">476</xref></sup></td><td>Promotes cell proliferation, invasion, EMT and cancer stem cell maintenance (Myc, MMP-9, Ctnnb1, JAK/Stat3 pathway, Wnt pathway, androgen receptor transcription)</td></tr><tr><td> SMYD4</td><td>ZMYND21</td><td>Suppressor</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR477">477</xref></sup></td><td>SMYD4 acts as a suppressor in tumorigenesis</td></tr><tr><td colspan="5">Others</td></tr><tr><td> DOT1L</td><td>KMT4</td><td>promoter</td><td>MLL-rearranged leukemia, colorectal cancer, breast cancer, ovarian cancer<sup><xref ref-type="bibr" rid="CR391">391</xref>,<xref ref-type="bibr" rid="CR478">478</xref>,<xref ref-type="bibr" rid="CR479">479</xref></sup></td><td>Increases EMT, cancer stemness and tumorigenic potential and is required for MLL rearrangement</td></tr><tr><td> SET8</td><td>KMT5A, SETD8, PR-set7</td><td>promoter</td><td>Breast cancer, prostate cancer, ovarian cancer, lung cancer<sup><xref ref-type="bibr" rid="CR480">480</xref>,<xref ref-type="bibr" rid="CR481">481</xref></sup></td><td>Promotes cell proliferation, migration, invasion, and EMT (MiR-502)</td></tr><tr><td> SUV4-20H2</td><td>KMT5C, MGC2705</td><td>Suppressor</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR482">482</xref></sup></td><td>SUV4-20H2 is downregulated in breast cancer</td></tr><tr><td> SetD6</td><td>/</td><td>Promoter</td><td>Colorectal cancer, bladder cancer, breast cancer<sup><xref ref-type="bibr" rid="CR483">483</xref>,<xref ref-type="bibr" rid="CR484">484</xref></sup></td><td>Promotes cell survival and colony formation and contributes to increased susceptibility to cancer</td></tr><tr><td> SET7/9</td><td>SETD7, KMT7</td><td>Suppressor</td><td>Breast cancer, gastric cancer, AML, lung cancer<sup><xref ref-type="bibr" rid="CR485">485</xref>–<xref ref-type="bibr" rid="CR487">487</xref></sup></td><td>Promotes cell proliferation, EMT and the generation of cancer stem cells; a low level of SET7/9 is correlated with clinical aggressiveness and worse prognosis (β-catenin stability)</td></tr><tr><td colspan="5"><italic>Histone methyltransferases (arginine): the writers for arginine</italic></td></tr><tr><td> PRMT1</td><td>ANM1, HCP1, IR1B4</td><td>Promoter</td><td>Breast cancer, colon cancer, gastric cancer, lung cancer<sup><xref ref-type="bibr" rid="CR488">488</xref>–<xref ref-type="bibr" rid="CR490">490</xref></sup></td><td>Promotes EMT, cancer cell migration, and invasion and is associated with chemosensitivity and poor clinical and histological parameters</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Pancreatic cancer<sup><xref ref-type="bibr" rid="CR491">491</xref></sup></td><td>Inhibits cell proliferation and invasion in pancreatic cancer</td></tr><tr><td> PRMT2</td><td>/</td><td>Suppressor</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR492">492</xref></sup></td><td>Induces cell cycle arrest and apoptosis in breast cancer</td></tr><tr><td> PRMT4</td><td>CARM1</td><td>Promoter</td><td>Ovarian cancer, breast cancer, liver cancer, colorectal cancer, prostate cancer<sup><xref ref-type="bibr" rid="CR450">450</xref>,<xref ref-type="bibr" rid="CR493">493</xref>,<xref ref-type="bibr" rid="CR494">494</xref></sup></td><td>Promotes cell proliferation and blocks cell differentiation (Wnt/β-catenin signaling)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Pancreatic cancer<sup><xref ref-type="bibr" rid="CR495">495</xref></sup></td><td>Inhibits glutamine metabolism and suppresses cancer progression</td></tr><tr><td> PRMT5</td><td>JBP1, SKB1, IBP72</td><td>Promoter</td><td>Breast cancer, prostate cancer, colorectal cancer, lung cancer<sup><xref ref-type="bibr" rid="CR496">496</xref>–<xref ref-type="bibr" rid="CR498">498</xref></sup></td><td>Promotes cell survival, proliferation, invasiveness and sensitivity to 5-Fluorouracil (5-FU) (SHARPIN-PRMT5-H3R2me1 axis)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR499">499</xref></sup></td><td>High PRMT5 expression favors a better prognosis in BC patients</td></tr><tr><td> PRMT6</td><td>HRMT1L6</td><td>Promoter</td><td>Prostate cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR500">500</xref>,<xref ref-type="bibr" rid="CR501">501</xref></sup></td><td>Is associated with cell apoptosis, invasiveness and viability (PI3K/AKT/mTOR pathway, H3R2me2as)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Hepatocellular carcinoma<sup><xref ref-type="bibr" rid="CR502">502</xref></sup></td><td>Negatively correlates with aggressive cancer features</td></tr><tr><td> PRMT7</td><td>FLJ10640, KIAA1933</td><td>Promoter</td><td>Lung cancer, breast cancer<sup><xref ref-type="bibr" rid="CR503">503</xref>,<xref ref-type="bibr" rid="CR504">504</xref></sup></td><td>Promotes cancer cell EMT and tumor metastasis</td></tr><tr><td> PRMT8</td><td>HRMT1L3, HRMT1L4</td><td>Promoter</td><td>Breast, ovarian and gastric cancer<sup><xref ref-type="bibr" rid="CR505">505</xref></sup></td><td>Overexpression of PRMT8 is correlated with decreased patient survival</td></tr><tr><td> PRMT9</td><td>FBXO11</td><td>Promoter</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR506">506</xref></sup></td><td>Fuels tumor formation via restraint of the p53/p21 pathway</td></tr><tr><td colspan="5"><italic>Methyl-histone recognition proteins: the readers</italic></td></tr><tr><td colspan="5">Chromodomain</td></tr><tr><td> HP1</td><td>/</td><td>Promoter</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR507">507</xref></sup></td><td>Overexpression of HP1 is associated with breast cancer progression</td></tr><tr><td> Chd1</td><td>/</td><td>Promoter</td><td>Prostate cancer<sup><xref ref-type="bibr" rid="CR508">508</xref></sup></td><td>Is associated with cell invasiveness, double-strand break repair and response to DNA-damaging therapy</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Prostate cancer<sup><xref ref-type="bibr" rid="CR509">509</xref></sup></td><td>Loss of MAP3K7 and CHD1 promotes an aggressive phenotype in prostate cancer</td></tr><tr><td colspan="5">WD40 repeat domain</td></tr><tr><td> WDR5</td><td>/</td><td>/</td><td>/</td><td></td></tr><tr><td colspan="5">MBT domain</td></tr><tr><td> BPTF</td><td>/</td><td>Promoter</td><td>Lung cancer, hepatocellular carcinoma<sup><xref ref-type="bibr" rid="CR510">510</xref>,<xref ref-type="bibr" rid="CR511">511</xref></sup></td><td>Promotes cell proliferation, migration, stem cell-like traits and invasion (miR-3666)</td></tr><tr><td> L3MBTL1</td><td>/</td><td>Suppressor</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR512">512</xref></sup></td><td>Expression of L3MBTL1 is associated with a low risk of disease recurrence and breast cancer-related death</td></tr><tr><td> ING2</td><td></td><td>Promoter</td><td>Colon cancer<sup><xref ref-type="bibr" rid="CR513">513</xref></sup></td><td>Increases invasion by enhancing MMP13 expression</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Lung cancer<sup><xref ref-type="bibr" rid="CR514">514</xref></sup></td><td>Suppresses tumor progression via regulation of p53</td></tr><tr><td>BHC80</td><td></td><td>Promoter</td><td>Prostate cancer<sup><xref ref-type="bibr" rid="CR515">515</xref></sup></td><td>Stimulates cell proliferation and tumor progression via the MyD88-p38-TTP pathway</td></tr><tr><td colspan="5"><italic>Tudor domains</italic></td></tr><tr><td>JMJD2A</td><td></td><td>Promoter</td><td>Breast cancer, liver cancer, colon cancer<sup><xref ref-type="bibr" rid="CR516">516</xref>,<xref ref-type="bibr" rid="CR517">517</xref></sup></td><td>Promotes cells apoptosis and proliferation and contributes to tumor progression (ARHI, miR372)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Bladder cancer<sup><xref ref-type="bibr" rid="CR518">518</xref></sup></td><td>Low JMJD2A correlates with poor prognostic features and predicts significantly decreased overall survival</td></tr><tr><td colspan="5"><italic>KDMs: the erasers</italic></td></tr><tr><td colspan="5">KDM1</td></tr><tr><td> KDM1A</td><td>LSD1</td><td>Promoter</td><td>Breast cancer, lung cancer, prostate cancer, liver cancer, pancreatic cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR519">519</xref>–<xref ref-type="bibr" rid="CR521">521</xref></sup></td><td>Contributes to cell proliferation and stem cell maintenance and self-renewal (p21, AR, HIF1α-dependent glycolytic process)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR522">522</xref></sup></td><td>Inhibits invasion and metastatic potential</td></tr><tr><td> KDM1B</td><td>LSD2</td><td>Promoter</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR523">523</xref></sup></td><td>Contributes to cancer progression and cancer stem cell enrichment</td></tr><tr><td colspan="5">KDM2/JHDM1</td></tr><tr><td> KDM2A</td><td>JHDM1A, CXXC8</td><td>Promoter</td><td>Breast cancer, gastric cancer, lung cancer, cervical cancer<sup><xref ref-type="bibr" rid="CR524">524</xref>–<xref ref-type="bibr" rid="CR526">526</xref></sup></td><td>Promotes cancer cell proliferation, metastasis, and invasiveness (HDAC3, TET2)</td></tr><tr><td> KDM2B</td><td>JHDM1B, FBXL10,</td><td>Promoter</td><td>Prostate cancer, breast cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR527">527</xref>,<xref ref-type="bibr" rid="CR528">528</xref></sup></td><td>Promotes cell migration, angiogenesis, and the self-renewal of cancer stem cells</td></tr><tr><td colspan="5">KDM3/JHDM2/JMJD1</td></tr><tr><td> KDM3A</td><td>JHDM2A, JMJD1A</td><td>Promoter</td><td>Colorectal cancer, ovarian cancer, breast cancer, prostate cancer, bladder cancer<sup><xref ref-type="bibr" rid="CR529">529</xref>–<xref ref-type="bibr" rid="CR531">531</xref></sup></td><td>Promotes cancer cell growth, metastasis, stemness and chemoresistance (<italic>c-Myc</italic>, Wnt/β-catenin signaling, glycolysis, HIF1α)</td></tr><tr><td> KDM3C</td><td>JHDM2C, JMJD1C</td><td>Promoter</td><td>Esophageal cancer, colorectal cancer<sup><xref ref-type="bibr" rid="CR532">532</xref>,<xref ref-type="bibr" rid="CR533">533</xref></sup></td><td>Promotes cancer cell proliferation and metastasis (YAP1 signaling, ATF-2)</td></tr><tr><td colspan="5">KDM4/JHMD3/JMJD2</td></tr><tr><td> KDM4A</td><td>JHDM3A, JMJD2A</td><td>Promoter</td><td>Breast cancer, liver cancer<sup><xref ref-type="bibr" rid="CR516">516</xref>,<xref ref-type="bibr" rid="CR534">534</xref></sup></td><td>Promotes cancer progression through repression of the tumor suppressor ARHI (miR372)</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Bladder cancer<sup><xref ref-type="bibr" rid="CR518">518</xref></sup></td><td>Downregulated in cancer tissues and significantly decreases as cancer progresses</td></tr><tr><td> KDM4B</td><td>JMJD2B</td><td>Promoter</td><td>Breast cancer, gastric cancer, ovarian cancer, colorectal cancer, prostate cancer<sup><xref ref-type="bibr" rid="CR535">535</xref>–<xref ref-type="bibr" rid="CR537">537</xref></sup></td><td>Promotes EMT and metastasis, and regulates the seeding and growth of peritoneal tumors; is involved in resistance to PI3K inhibition (p-ERK, β-catenin)</td></tr><tr><td> KDM4C</td><td>JMJD2C, GASC1</td><td>Promoter</td><td>Breast cancer, pancreatic cancer<sup><xref ref-type="bibr" rid="CR538">538</xref>,<xref ref-type="bibr" rid="CR539">539</xref></sup></td><td>Promotes cancer progression (HIF-1α, miR-335-5p)</td></tr><tr><td> KMD4D</td><td>JMJD2D</td><td>Promoter</td><td>Colorectal cancer<sup><xref ref-type="bibr" rid="CR540">540</xref></sup></td><td>Promotes cell proliferation and tumor growth (β-catenin)</td></tr><tr><td colspan="5">KDM5/JARID</td></tr><tr><td> KDM5A</td><td>JARID1A, RBP2</td><td>Promoter</td><td>Breast cancer, colorectal cancer, cervical cancer<sup><xref ref-type="bibr" rid="CR541">541</xref>,<xref ref-type="bibr" rid="CR542">542</xref></sup></td><td>Promotes proliferative activity and invasion, and inhibition of KDM5A causes growth arrest at the G1 phase (<italic>c-Myc</italic>)</td></tr><tr><td> KDM5B</td><td>JARID1B, RBP2-like</td><td>Promoter</td><td>Colorectal cancer, lung cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR543">543</xref></sup></td><td>Promotes cell proliferation, metastasis, and expression of CSCs, and inhibition of KDM5B results in cell cycle arrest, apoptosis, and senescence (E2F/RB pathway)</td></tr><tr><td> KDM5C</td><td>JARID1C, SMCX</td><td>Promoter</td><td>Prostate cancer, lung cancer<sup><xref ref-type="bibr" rid="CR544">544</xref></sup></td><td>Overexpression of KDM5C predicts therapy failure and is associated with cancer cell growth, migration and invasion</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Colon cancer<sup><xref ref-type="bibr" rid="CR545">545</xref></sup></td><td>Inhibits the multidrug resistance of colon cancer cell lines by downregulating ABCC1</td></tr><tr><td> KDM5D</td><td>JARID1D, SMCY</td><td>Promoter</td><td>Gastric cancer<sup><xref ref-type="bibr" rid="CR546">546</xref></sup></td><td>Promotes cell proliferation and EMT</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Prostate cancer<sup><xref ref-type="bibr" rid="CR547">547</xref></sup></td><td>Loss of KDM5D expression induces resistance to docetaxel</td></tr><tr><td> JARID2</td><td>JUMONJI</td><td>Promoter</td><td>Bladder cancer, lung and colon cancers<sup><xref ref-type="bibr" rid="CR548">548</xref>,<xref ref-type="bibr" rid="CR549">549</xref></sup></td><td>Regulates cancer cell EMT and stem cell maintenance and is associated with poor survival</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Prostate cancer<sup><xref ref-type="bibr" rid="CR550">550</xref></sup></td><td>Inhibits cell proliferation, migration, and tumor development via inhibition of Axl</td></tr><tr><td colspan="5">KDM6/UT</td></tr><tr><td> KDM6A</td><td>UTX</td><td>Promoter</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR447">447</xref></sup></td><td>Promotes cell proliferation and invasiveness</td></tr><tr><td></td><td></td><td>Suppressor</td><td>Bladder cancer, pancreatic cancer<sup><xref ref-type="bibr" rid="CR551">551</xref>,<xref ref-type="bibr" rid="CR552">552</xref></sup></td><td>KDM6A loss induces squamous-like, metastatic pancreatic cancer</td></tr><tr><td> KDM6B</td><td>JMJD3</td><td>Promoter</td><td>Ovarian cancer, breast cancer, gastric cancer<sup><xref ref-type="bibr" rid="CR553">553</xref>,<xref ref-type="bibr" rid="CR554">554</xref></sup></td><td>High expression of KDM6B is correlated with poor prognosis</td></tr><tr><td> KDM6C</td><td>UTY</td><td>Suppressor</td><td>Bladder cancer<sup><xref ref-type="bibr" rid="CR555">555</xref></sup></td><td>UTY-knockout cells have increased cell proliferation compared to wild-type cells</td></tr><tr><td colspan="5">KDM7/PHF</td></tr><tr><td> KDM7A</td><td>JHDM1D</td><td>Promoter</td><td>Prostate cancer<sup><xref ref-type="bibr" rid="CR556">556</xref></sup></td><td>Promotes cell proliferation and upregulated androgen receptor activity</td></tr><tr><td> KDM7C</td><td>PHF2, JHDM1E</td><td>Suppressor</td><td>N/A<sup><xref ref-type="bibr" rid="CR420">420</xref></sup></td><td>Is a suppressor and promotes p53-driven gene expression</td></tr><tr><td> KDM7B</td><td>PHF8, JHDM1F</td><td>Promoter</td><td>Prostate cancer, gastric cancer, lung cancer, leukemia, colorectal cancer<sup><xref ref-type="bibr" rid="CR557">557</xref>–<xref ref-type="bibr" rid="CR559">559</xref></sup></td><td>Promotes cell proliferation, migration and invasion, and high PHF8 expression predicts poor survival (miR-488)</td></tr><tr><td colspan="5">Others</td></tr><tr><td> JMJD5</td><td>KDM8</td><td>Promoter</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR560">560</xref>,<xref ref-type="bibr" rid="CR561">561</xref></sup></td><td>Promotes metastasis and indicates a poor prognosis; is required for cell cycle progression via because of its actions in the cyclin A1 coding region.</td></tr><tr><td> RSBN1</td><td>KDM9</td><td>Promoter</td><td>Breast cancer<sup><xref ref-type="bibr" rid="CR562">562</xref></sup></td><td>Is a new potential HIF target</td></tr><tr><td> JMJD6</td><td>PSR, PTDSR</td><td>Promoter</td><td>Breast cancer, oral cancer, lung cancer<sup><xref ref-type="bibr" rid="CR563">563</xref>–<xref ref-type="bibr" rid="CR565">565</xref></sup></td><td>Promotes cancer cell proliferation, EMT and motility, and maintains cancer cell stemness properties (autophagy pathway, WNT/β-catenin pathway)</td></tr><tr><td> PADI4</td><td>/</td><td>Promoter</td><td>Breast cancer, esophageal cancer<sup><xref ref-type="bibr" rid="CR566">566</xref></sup></td><td>Promotes cancer progression and is correlated with pathological classification (c-Fos)</td></tr></tbody></table><table-wrap-foot><p><italic>EMT</italic> epithelial-mesenchymal transition, <italic>CSC</italic> cancer stem cell, <italic>EGFR</italic> epidermal growth factor receptor, <italic>MMP</italic> matrix metalloproteinase, <italic>PI3K</italic> phosphatidylinositol 3-kinase</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec13"><title>Methyl-histone recognition proteins</title><p id="Par28">“Readers” of histone methylation contain several specific domains recognizing lysine or arginine methylation, such as a chromodomain,<sup><xref ref-type="bibr" rid="CR394">394</xref></sup> the WD40 repeat, the MBT (malignant brain tumor) domain, the Tudor domain<sup><xref ref-type="bibr" rid="CR395">395</xref></sup> and the PHD (plant homeodomain) finger motif.<sup><xref ref-type="bibr" rid="CR396">396</xref></sup> Representative chromodomain-containing proteins in humans are HP1 and Chd1, which can recognize H3K9me and H3K27me, respectively.<sup><xref ref-type="bibr" rid="CR394">394</xref>,<xref ref-type="bibr" rid="CR397">397</xref></sup> WDR5 is a protein containing WD40 repeats. In addition to H3K4me, WDR5 prefers to bind to H3K4me2 via a histone-methylating complex and is required for maintaining H3K4me3.<sup><xref ref-type="bibr" rid="CR395">395</xref></sup> Later, WDR5 was shown to directly read H3R2, a “WIN” motif of MLL1, as well as symmetrical H3R2 dimethylation through the WD40 domain.<sup><xref ref-type="bibr" rid="CR398">398</xref></sup> L3MBTLs are a group of proteins containing three MBT repeat domains. L3MBTL1 represses gene expression via monomethylation or dimethylation of H4K20 or H1BK26.<sup><xref ref-type="bibr" rid="CR399">399</xref></sup> BPTF, RAG2, PYGO, and the tumor suppressor ING2 are representative proteins containing PHD finger motifs. They are all able to recognize and bind to H3K4me3.<sup><xref ref-type="bibr" rid="CR400">400</xref></sup> Intriguingly, DNMT3L and BHC80 also possess a PHD finger motif, but they selectively bind to unmethylated H3K4.<sup><xref ref-type="bibr" rid="CR401">401</xref>,<xref ref-type="bibr" rid="CR402">402</xref></sup> There are a number of proteins containing Tudor domains, with a representative protein being JMJD2A. JMJD2A is a histone demethylase that equally binds to H3K4me3 and H4K20me3<sup><xref ref-type="bibr" rid="CR403">403</xref></sup> (Table <xref rid="Tab3" ref-type="table">3</xref>).</p></sec><sec id="Sec14"><title>Histone demethylases</title><p id="Par29">The identification of histone demethylases (HDMs or KDMs) has lagged behind that of HMTs. Thus far, KDMs can be classified into two groups. The amine-oxidase type lysine-specific demethylases (LSDs) and the highly conserved JumonjiC (JMJC) domain-containing histone demethylases. LSD1 and LSD2, also known as KDM1A and B, are flavin adenine dinucleotide (FAD)-dependent amine oxidases that can only demethylate monomethylated and dimethylated lysine residues. LSD1 has been identified to specifically activate androgen receptor (AR) target genes along with AR by demethylating H3K9.<sup><xref ref-type="bibr" rid="CR404">404</xref></sup> The human genome codes more than 30 JMJC-containing KDMs that are able to remove methyl groups from all three methyl-lysine states. JHDM1A was the first characterized JMJC domain-containing HDM and specifically demethylates H3K36me2 and H3K36me1.<sup><xref ref-type="bibr" rid="CR405">405</xref></sup> Not all JMJC domain-containing proteins are able to demethylate histone proteins, such as HIF1AN and the transmembrane phosphatidylserine receptor PTDSR. JMJC-containing HDMs can be divided into six families:<sup><xref ref-type="bibr" rid="CR360">360</xref></sup> the JHDM1, JHDM2 (JMJD1), JHMD3 (JMJD2), JARID, PHF, and UT families. Notably, not all of these families possess the ability of histone demethylation. However, some JMJC-containing proteins, including those that are not included in these six families, contain one or more methylated-histone-binding domains. Their potential to demethylate methyl-lysine or methyl-arginine must be investigated. In addition to demethylases for lysine residues, JMJD6 is the first described arginine demethylase and lysine hydroxylase. It can remove methyl groups from H3R2 and H4R3.<sup><xref ref-type="bibr" rid="CR406">406</xref></sup> Another kind of protein is peptidylarginine deiminases (PADs or PADIs) or protein-arginine deiminases, which are able to convert arginine and monomethylated arginine to citrulline.<sup><xref ref-type="bibr" rid="CR407">407</xref></sup></p><p id="Par30">LSD1 (KDM1A) is one of the best-studied KDMs and has been found to be increased in multiple cancers. Inhibition of LSD1 leads to global H3K4 methylation and promotes differentiation of neuroblastoma cells.<sup><xref ref-type="bibr" rid="CR408">408</xref></sup> Unlike KDM1A, KDM1B is mostly involved in growing oocytes with a restricted expression pattern.<sup><xref ref-type="bibr" rid="CR409">409</xref></sup> Similar to the dual roles of LSD1, members of the KDM2 family can either promote tumor formation or inhibit tumorigenesis.<sup><xref ref-type="bibr" rid="CR410">410</xref></sup> Through dimethylating H3K36 in DUSP3 (dual specific phosphatase 3), KDM2A activates ERK1/2 expression in lung cancer cells.<sup><xref ref-type="bibr" rid="CR411">411</xref></sup> Knockout of KDM2B in breast cancer downregulates the tumor stem cell markers ALDH and CD44 via the repression of polycomb complexes. KDM2B is also overexpressed in pancreatic ductal adenocarcinoma (PDAC) and cooperates with KrasG12D to promote PDAC formation in mouse models.<sup><xref ref-type="bibr" rid="CR412">412</xref></sup> The LSD1 and KDM2 family possesses context-dependent tumor-promoting and -inhibiting functions, which might depend on the different features of various cancers and the specific substrates of the enzymes. Therefore, further studies should take the dual roles of these enzymes into consideration. KDM3A, induced by hypoxia and nutrient starvation within the tumor microenvironment, shows carcinogenic effects via the promotion of tumor cell migration and invasion. Inhibition of KDM3A downregulates tumor-associated angiogenesis and macrophage infiltration.<sup><xref ref-type="bibr" rid="CR413">413</xref>,<xref ref-type="bibr" rid="CR414">414</xref></sup> KDM3C is required for MLL-AF9 leukemia maintenance and is mutated in patients with intracranial germline tumors.<sup><xref ref-type="bibr" rid="CR415">415</xref>,<xref ref-type="bibr" rid="CR416">416</xref></sup> KDM4A, KDM4B, and KDM4C have shown increased expression in prostate cancer with decreased levels of H3K9me2/3 and increased levels of H3K9me1.<sup><xref ref-type="bibr" rid="CR417">417</xref></sup> H3K9me3 is thought to be a hallmark of heterochromatic areas of the genome. In addition, KDM4 family members were the first identified demethylases targeting trimethylated lysines. Aberrant expression of KDM4 family members might lead to instability of the genome and become involved in tumorigenesis.<sup><xref ref-type="bibr" rid="CR410">410</xref></sup> Members of the KDM6 family usually act as tumor suppressors and are thought to cause cell growth arrest.<sup><xref ref-type="bibr" rid="CR418">418</xref></sup> For example, the tumor suppressor proteins p16INK4A and p14ARF, encoded by the INK4A-ARF locus, are repressed by H3K27me3. When stimulated by oncogenic factors, KDM6B is recruited to the INK4A-ARF locus and activates the transcription of these two tumor suppressors.<sup><xref ref-type="bibr" rid="CR419">419</xref></sup> In colorectal cancer, KDM7C is required for the efficacy of oxaliplatin and doxorubicin and for the activation of p53<sup><xref ref-type="bibr" rid="CR420">420</xref></sup> (Table <xref rid="Tab3" ref-type="table">3</xref>).</p></sec></sec></sec><sec id="Sec15"><title>Noncoding RNA</title><p id="Par31">Epigenetic related noncoding RNAs (ncRNAs) include microRNAs (miRNAs), small interfering RNA (siRNAs), Piwi-interacting RNA (piRNAs), and long noncoding RNAs (lncRNAs). MiRNAs, one of the most studied ncRNAs, are small RNAs between 19 and 22 nucleotides in length that play important roles in the regulation of gene expression by controlling mRNA translation. Intriguingly, the regions that miRNAs usually target are frequently associated with carcinogenesis.<sup><xref ref-type="bibr" rid="CR567">567</xref></sup> Generally, they can be divided into tumor-promoting and tumor-suppressing miRNAs. During tumorigenesis, oncogenic miRNAs such as miR-155, miR-21 and miR-17-92 are usually overexpressed, and tumor-suppressive miRNAs such as miR-15-16 are downregulated.<sup><xref ref-type="bibr" rid="CR568">568</xref></sup> There is another type of miRNA, cellular context-dependent miRNAs, functioning in tumorigenesis. For example, miR-146 has been shown to be overexpressed in multiple cancers, whereas a recent study has proven that miR-146 can reduce the expression of BRCA1.<sup><xref ref-type="bibr" rid="CR568">568</xref>,<xref ref-type="bibr" rid="CR569">569</xref></sup> Meanwhile, the expression of proteins and enzymes is also regulated by certain miRNAs. MiR-101 directly represses EZH2, and abnormal downregulation of miR-101 has been observed in cancers.<sup><xref ref-type="bibr" rid="CR570">570</xref>,<xref ref-type="bibr" rid="CR571">571</xref></sup> The expression of the miR-29 family is inversely correlated with that of DNMT3A and -3B in lung cancer tissues. Forced expression of miR-29 inhibits tumorigenesis by inducing reexpression of methylation-silenced tumor suppressor genes.<sup><xref ref-type="bibr" rid="CR572">572</xref></sup> LncRNAs are another large group of noncoding RNAs that play a vital role in tumorigenesis. Some lncRNAs are cancer type-specific, such as PCGEM1 in prostate cancer and HEIH in hepatocellular carcinoma.<sup><xref ref-type="bibr" rid="CR573">573</xref>,<xref ref-type="bibr" rid="CR574">574</xref></sup> Many aberrant lncRNAs have been discovered in various cancers. Dysregulation of HOTAIR has been found in lung, pancreatic, and colorectal cancer.<sup><xref ref-type="bibr" rid="CR575">575</xref>–<xref ref-type="bibr" rid="CR577">577</xref></sup></p><p id="Par32">Therefore, ncRNAs can either be directly involved in tumorigenesis or indirectly affect tumor development by participating in other epigenetic events.</p></sec><sec id="Sec16"><title>Inhibitors and clinical trials</title><p id="Par33">Unlike genetic mutations, epigenetic alterations are reversible. Given the importance of epigenetic marks in tumorigenesis, the availability of corresponding inhibitors has attracted extensive attention. Meanwhile, epigenetic regulation of a gene usually requires more than one epigenetic event. Currently, there are six epigenetic drugs approved for clinical use by the FDA (Table <xref rid="Tab4" ref-type="table">4</xref>).<table-wrap id="Tab4"><label>Table 4</label><caption><p>Epigenetic drugs approved by the FDA.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Compound</th><th>Synonym</th><th>Clinical name</th><th>Condition</th><th>Approved year</th><th>Company</th></tr></thead><tbody><tr><td>Azacitidine</td><td>5-Azacitidine, 5-Aza-CR</td><td>Vidaza</td><td>MDS</td><td>U.S. FDA (2004)</td><td>Pharmion Corporation</td></tr><tr><td>5-Aza-2′-deoxycytidine</td><td>5-Aza-CdR, decitabine</td><td>Dacogen</td><td>MDS</td><td>U.S. FDA (2006)</td><td>Janssen Pharmaceuticals</td></tr><tr><td>Suberoylanilide hydroxamic acid (SAHA)</td><td>Vorinostat</td><td>Zolinza</td><td>CTCL</td><td>U.S. FDA (2006)</td><td>Merck</td></tr><tr><td>Romidepsin</td><td>Depsipeptide, FK-229, FR901228</td><td>Istodax</td><td>CTCL</td><td>U.S. FDA (2009)</td><td>Celgene</td></tr><tr><td>Belinostat</td><td>PXD101</td><td>Beleodaq</td><td>PTCL</td><td>U.S. FDA (2014)</td><td>TopoTarget</td></tr><tr><td>Panobinostat</td><td>LBH589</td><td>Farydak</td><td>Multiple myeloma</td><td>U.S. FDA (2015)</td><td>Novartis</td></tr><tr><td>Chidamide</td><td>Tucidinostat, HBI-8000</td><td>Epidaza</td><td>PTCL</td><td>China FDA (2015)</td><td>Chipscreen Biosciences</td></tr></tbody></table><table-wrap-foot><p><italic>FDA</italic> Food and Drug Administration, <italic>MDS</italic> myelodysplastic syndrome, <italic>CTCL</italic> cutaneous T-cell lymphoma, <italic>PTCL</italic> peripheral T-cell lymphoma</p></table-wrap-foot></table-wrap></p><sec id="Sec17"><title>Targeting DNA methylation</title><p id="Par34">Blockade of DNMTs is the most effective way to prevent aberrant DNA hypermethylation. However, until now, targeting of the methyltransferase enzymes still lacks specificity and even causes hypomethylation of the global genome.<sup><xref ref-type="bibr" rid="CR578">578</xref></sup> Complete deletion of DNMT1 in mice results in embryonic lethality.<sup><xref ref-type="bibr" rid="CR579">579</xref></sup> Knockout of DNMT1 in fibroblast cells causes aberrant expression of 10% of genes and p53-dependent death.<sup><xref ref-type="bibr" rid="CR580">580</xref></sup> Administration of DNA methylation inhibitors results in tumorigenesis in male Fischer rats.<sup><xref ref-type="bibr" rid="CR581">581</xref></sup> Regulation of DNA methylation is vital in cell survival and function, and in addition to the specificity needed and the side effect associated, it is hard to identify proper drugs.</p><p id="Par35">DNA methylation inhibitors can be divided into two groups: nucleoside analogs and nonnucleoside analogs. Nucleoside analogs have a modified cytosine ring and can be turned into nucleotides and incorporated into newly synthesized DNA or RNA. DNA methyltransferases are bound by covalent complexes with the analogs, which inhibits DNA methylation. 5-Azacitidine (5-Aza-CR) and 5-aza-2′-deoxycytidine (5-Aza-CdR) are currently the two most studied and promising demethylation agents.<sup><xref ref-type="bibr" rid="CR582">582</xref></sup> 5-Aza-CR and zebularine are ribonucleoside analogs that can be phosphorylated to be able to incorporate into RNA. However, they can also be incorporated into DNA via the ribonucleotide reductase pathway. 5-Azacitidine, an analog of cytidine, is an injectable suspension for the treatment of myelodysplastic syndromes (MDSs). It promotes cell differentiation, demethylation, and reexpression of inactivated genes.<sup><xref ref-type="bibr" rid="CR583">583</xref></sup> The 5-azacitidine side effects include fetal abnormalities<sup><xref ref-type="bibr" rid="CR584">584</xref></sup> and decreased male fertility, especially at high doses, but its analog, 6-azacytidine, does not show such effects.<sup><xref ref-type="bibr" rid="CR585">585</xref></sup> Notably, after treating the noninvasive breast cancer cell lines MCF-7 and ZR-75-1 with azacytidine, the cells gained invasive abilities due to the hypomethylation of several prometastasis genes.<sup><xref ref-type="bibr" rid="CR586">586</xref></sup> Decitabine (5-Aza-CdR) and 5-fluoro-2′-deoxycytidine (5-F-CdR) are deoxyribonucleoside analogs that are capable of incorporating into DNA following phosphorylation. Decitabine (5-aza-2′-deoxycytidine) inhibits DNA methylation in a dosage-dependent manner. It can reactivate silenced genes at low doses but gains cytotoxicity at high doses, while myelosuppression is the major side effect at all doses.<sup><xref ref-type="bibr" rid="CR587">587</xref></sup>. Dihydro-5-azacytidine (DHAC) is a biologically active and chemically stable analog of 5-azacitidine with decreased toxicity.<sup><xref ref-type="bibr" rid="CR588">588</xref>,<xref ref-type="bibr" rid="CR589">589</xref></sup> Because of its hydrolytic stability, it may be administrated via prolonged i.v. infusion, potentially eliminating the acute toxicities caused by administration of 5-azacytidine.<sup><xref ref-type="bibr" rid="CR590">590</xref></sup> Zebularine is a potential oral DNA-demethylating drug with stability in acidic environments and in aqueous solutions.<sup><xref ref-type="bibr" rid="CR591">591</xref></sup> However, the near millimolar dose requirements and the limited bioavailability in rodents (<7%) and primates (<1%) leave zebularine far from clinical translation.<sup><xref ref-type="bibr" rid="CR592">592</xref></sup></p><p id="Par36">Among the drugs discussed, 5-Aza-CR<sup><xref ref-type="bibr" rid="CR593">593</xref></sup> and 5-Aza-CdR<sup><xref ref-type="bibr" rid="CR594">594</xref></sup> have already been approved by the US Food and Drug Administration (FDA) for the treatment of certain subtypes of MDS and chronic myelomonocytic leukemia. Because of their intrinsic preference for newly synthetic DNA, they tend to affect dividing cells, i.e., cancer cells.<sup><xref ref-type="bibr" rid="CR595">595</xref></sup> Ongoing preclinical experiments and clinical trials are exploring their efficacy in solid tumors. The common side effects of these nucleoside-like analogs are mutagenic risk and genomic instability. Nonnucleoside analogs are capable of avoiding these side effects.</p><p id="Par37">Currently, many nonnucleoside analogs have been developed to prevent DNA from aberrant hypermethylation. These drugs are usually small molecular inhibitors and directly target catalytic sites rather than incorporating into DNA. Based on a three-dimensional model of DNMT1, RG108 was designed to block the activity of this enzyme and cause demethylation.<sup><xref ref-type="bibr" rid="CR596">596</xref></sup> Psammaplin is a group of natural extracts from the sponge <italic>Pseudoceratina purpurea</italic> and is capable of inhibiting both DNA methyltransferases and histone deacetylases with mild cytotoxicity.<sup><xref ref-type="bibr" rid="CR597">597</xref></sup> Similarly, EGCG ((-)-epigallocatechin-3-gallate) is the major polyphenol from green tea and reversibly demethylates methyl-DNA, resulting in the reactivation of multiple key genes, including hMLH1, P16, and RA, in colon, esophageal, and prostate cancer cell lines.<sup><xref ref-type="bibr" rid="CR598">598</xref></sup> Both hydralazine and procainamide, two drugs associated with lupus-like autoimmune diseases, can inhibit DNA methylation and induce self-reactivity in cloned T-cell lines.<sup><xref ref-type="bibr" rid="CR599">599</xref></sup> They have promising tumor suppressor-reactivating and antitumor actions in breast cancer.<sup><xref ref-type="bibr" rid="CR600">600</xref>,<xref ref-type="bibr" rid="CR601">601</xref></sup> Another strategy is developing antisense oligonucleotides to inhibit DNMT transcription. MG98 is a second-generation phosphorothioate antisense oligodeoxynucleotide that prevents DNMT1 mRNA translation effects but has no obvious antitumor effect.<sup><xref ref-type="bibr" rid="CR602">602</xref></sup> It has been under investigation in preclinical experiments and phase I/II clinical trials, especially in solid tumors.<sup><xref ref-type="bibr" rid="CR603">603</xref>,<xref ref-type="bibr" rid="CR604">604</xref></sup> Of note, in a systemic analysis comparing nonnucleoside inhibitors with 5-Aza-CdR, the latter showed better efficacy in DNA demethylation inhibition.<sup><xref ref-type="bibr" rid="CR605">605</xref></sup></p><p id="Par38">To date, hundreds of clinical trials have investigated the effects of anti-DNA methylation therapy for various cancers (Table <xref rid="Tab5" ref-type="table">5</xref>).<table-wrap id="Tab5"><label>Table 5</label><caption><p>Important ongoing clinical trials with DNA methylation-targeted therapies.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Condition</th><th>Design</th><th>Sample size</th><th>Phase</th><th>Current status</th><th>NCT</th></tr></thead><tbody><tr><td colspan="6"><italic>Azacitidine (5-azacitidine)-based trials</italic></td></tr><tr><td> High-risk MDS</td><td>Azacitidine</td><td>44</td><td>IV</td><td>Completed</td><td>NCT01201811</td></tr><tr><td> Low-risk MDS</td><td>Azacitidine</td><td>216</td><td>III</td><td>Active, not recruiting</td><td>NCT01566695</td></tr><tr><td> High-risk MDS</td><td>Azacitidine</td><td>358</td><td>III</td><td>Completed</td><td>NCT00071799</td></tr><tr><td> CML</td><td>Azacitidine</td><td>11</td><td>II</td><td>Completed</td><td>NCT01350947</td></tr><tr><td> AML, MDS</td><td>Azacitidine</td><td>187</td><td>III</td><td>Completed</td><td>NCT00887068</td></tr><tr><td> Relapsed or refractory T-cell lymphoma</td><td>Azacitidine</td><td>20</td><td>III</td><td>Recruiting</td><td>NCT03703375</td></tr><tr><td> AML with complete remission</td><td>Azacitidine</td><td>472</td><td>III</td><td>Active, not recruiting</td><td>NCT01757535</td></tr><tr><td> Recurrent IDH1/2-mutated glioma</td><td>Azacitidine</td><td>63</td><td>II</td><td>Not yet</td><td></td></tr><tr><td> recruiting</td><td>NCT03666559</td><td></td><td></td><td></td><td></td></tr><tr><td> Prostate cancer</td><td>Azacytidine</td><td>36</td><td>II</td><td>Completed</td><td>NCT00384839</td></tr><tr><td> Head and neck squamous cell carcinoma</td><td>Azacitidine</td><td>25</td><td>II</td><td>Recruiting</td><td>NCT02178072</td></tr><tr><td> Locally advanced or metastatic nasopharyngeal carcinoma</td><td>Azacitidine</td><td>36</td><td>II</td><td>Completed</td><td>NCT02269943</td></tr><tr><td> Pancreatic cancer</td><td>Azacitidine</td><td>80</td><td>II</td><td>Recruiting</td><td>NCT01845805</td></tr><tr><td> Solid tumors and hematological disorders</td><td>Azacitidine</td><td>125</td><td>II</td><td>Recruiting</td><td>NCT02494258</td></tr><tr><td> AML</td><td>Azacitidine + venetoclax</td><td>42</td><td>II</td><td>Recruiting</td><td>NCT03466294</td></tr><tr><td> AML</td><td>Azacitidine + venetoclax</td><td>30</td><td>II</td><td>Recruiting</td><td>NCT03573024</td></tr><tr><td> AML</td><td>Azacitidine + venetoclax</td><td>400</td><td>III</td><td>Recruiting</td><td>NCT02993523</td></tr><tr><td> AML, MDS</td><td>Azacitidine + eltrombopag</td><td>25</td><td>II</td><td>Completed</td><td>NCT01488565</td></tr><tr><td> MDS</td><td>Azacitidine + eltrombopag</td><td>356</td><td>III</td><td>Terminated</td><td>NCT02158936</td></tr><tr><td> MDS</td><td>Azacitidine + APR-246</td><td>156</td><td>III</td><td>Recruiting</td><td>NCT03745716</td></tr><tr><td> AML, MDS</td><td>Azacitidine + DLI</td><td>30</td><td>II</td><td>Completed</td><td>NCT01541280</td></tr><tr><td> AML/MDS</td><td>Azacitidine + lenalidomide</td><td>72</td><td>II</td><td>N/A</td><td>NCT01556477</td></tr><tr><td> High-risk MDS with 5q deletion</td><td>Azacytidine + lenalidomide</td><td>50</td><td>II</td><td>Completed</td><td>NCT01088373</td></tr><tr><td> AML</td><td>Azacitidine + lenalidomide</td><td>88</td><td>II</td><td>Completed</td><td>NCT01358734</td></tr><tr><td> Elderly patients with AML</td><td>Azacitidine + lenalidomide</td><td>120</td><td>II</td><td>Completed</td><td>NCT01301820</td></tr><tr><td> Refractory AML</td><td>Azacitidine + lenalidomide</td><td>37</td><td>II</td><td>Completed</td><td>NCT01743859</td></tr><tr><td> MDS, CMML and AML relapsing after allo-HSCT</td><td>Azacitidine + lenalidomide + DLI</td><td>50</td><td>II</td><td>Active, not recruiting</td><td>NCT02472691</td></tr><tr><td> MDS with excess blasts 2</td><td>Azacitidine + vosaroxin</td><td>168</td><td>II</td><td>Recruiting</td><td>NCT03338348</td></tr><tr><td> AML</td><td>Azacitidine vs conventional care regimen</td><td>488</td><td>III</td><td>Completed</td><td>NCT01074047</td></tr><tr><td> AML, MDS with FLT3-ITD mutation</td><td>Azacitidine + sorafenib</td><td>17</td><td>II</td><td>Completed</td><td>NCT02196857</td></tr><tr><td> Advanced solid tumors</td><td>Azacitidine + durvalumab</td><td>60</td><td>II</td><td>Recruiting</td><td>NCT02811497</td></tr><tr><td> High-risk MDS, AML</td><td>Azacitidine + durvalumab</td><td>213</td><td>II</td><td>Active, not recruiting</td><td>NCT02775903</td></tr><tr><td> MDS patients with excess blasts, progressing</td><td>Azacitidine + rigosertib</td><td>67</td><td>III</td><td>Active, not recruiting</td><td>NCT01928537</td></tr><tr><td> AML, MDS, CML</td><td>Azacitidine + HAG regimen</td><td>120</td><td>III</td><td>Not yet</td><td></td></tr><tr><td> recruiting</td><td>NCT03873311</td><td></td><td></td><td></td><td></td></tr><tr><td> Refractory or relapsed AML</td><td>Azacitidine + lirilumab</td><td>37</td><td>II</td><td>Completed</td><td>NCT02399917</td></tr><tr><td> AML</td><td>Azacitidine + induction therapy</td><td>336</td><td>II</td><td>N/A</td><td>NCT01180322</td></tr><tr><td> AML with NPM1 mutation</td><td>Azacitidine + pembrolizumab</td><td>28</td><td>II</td><td>Not yet recruiting</td><td>NCT03769532</td></tr><tr><td> Pancreatic cancer</td><td>Azacitidine + pembrolizumab</td><td>31</td><td>II</td><td>Recruiting</td><td>NCT03264404</td></tr><tr><td> Metastatic melanoma</td><td>Azacitidine + pembrolizumab</td><td>71</td><td>II</td><td>Recruiting</td><td>NCT02816021</td></tr><tr><td> MDS</td><td>Azacitidine + pembrolizumab</td><td>40</td><td>II</td><td>Recruiting</td><td>NCT03094637</td></tr><tr><td> Chemorefractory metastatic colorectal cancer</td><td>Azacitidine + pembrolizumab</td><td>31</td><td>II</td><td>Active, not recruiting</td><td>NCT02260440</td></tr><tr><td> Advanced or metastatic non-small-cell lung cancer</td><td>Azacitidine + pembrolizumab</td><td>100</td><td>II</td><td>Active, not recruiting</td><td>NCT02546986</td></tr><tr><td> Platinum-resistant ovarian cancer</td><td>Azacitidine + pembrolizumab</td><td>20</td><td>II</td><td>Recruiting</td><td>NCT02900560</td></tr><tr><td> MDS</td><td>Azacitidine + lintuzumab</td><td>7</td><td>II</td><td>Terminated</td><td>NCT00997243</td></tr><tr><td> Prostate cancer</td><td>Azacitidine + ATRA</td><td>20</td><td>II</td><td>Recruiting</td><td>NCT03572387</td></tr><tr><td> Recurrent or refractory disease with IDH2 mutation</td><td>Azacitidine + enasidenib</td><td>50</td><td>II</td><td>Recruiting</td><td>NCT03683433</td></tr><tr><td> High-risk MDS with IDH2 mutation</td><td>Azacitidine + enasidenib</td><td>105</td><td>II</td><td>Recruiting</td><td>NCT03383575</td></tr><tr><td> Elderly patients with AML</td><td>Azacitidine + standard therapy</td><td>214</td><td>II</td><td>Completed</td><td>NCT00915252</td></tr><tr><td> Refractory or relapsed AML</td><td>Azacitidine + avelumab</td><td>52</td><td>I/II</td><td>Recruiting</td><td>NCT02953561</td></tr><tr><td> AML, MDS, CML</td><td>Azacitidine + pevonedistat</td><td>450</td><td>III</td><td>Recruiting</td><td>NCT03268954</td></tr><tr><td> Relapsed or refractory AML</td><td>Azacitidine + pevonedistat</td><td>72</td><td>II</td><td>Not yet recruiting</td><td>NCT03745352</td></tr><tr><td> High-risk MDS, AML, CML</td><td>Azacitidine + pevonedistat</td><td>120</td><td>II</td><td>Active, not recruiting</td><td>NCT02610777</td></tr><tr><td> AML without remission after allogeneic stem cell transplantation</td><td>Azacitidine + pevonedistat</td><td>30</td><td>II</td><td>Recruiting</td><td>NCT03709576</td></tr><tr><td> MDS</td><td>Azacitidine + pevonedistat</td><td>71</td><td>II</td><td>Recruiting</td><td>NCT03238248</td></tr><tr><td> Elderly patients with AML</td><td>Azacitidine + gemtuzumab ozogamicin</td><td>133</td><td>II</td><td>Active, not recruiting</td><td>NCT00658814</td></tr><tr><td> Recurrent and resectable osteosarcoma</td><td>Azacitidine + nivolumab</td><td>51</td><td>I/II</td><td>Not yet recruiting</td><td>NCT03628209</td></tr><tr><td> Childhood relapsed/refractory AML</td><td>Azacitidine + nivolumab</td><td>26</td><td>I/II</td><td>Not yet recruiting</td><td>NCT03825367</td></tr><tr><td> Elderly patients with AML or high-risk MDS</td><td>Azacitidine/decitabine + nivolumab or midostaurin</td><td>1670</td><td>II/III</td><td>Suspended</td><td>NCT03092674</td></tr><tr><td> Refractory/relapsed AML</td><td>Azacitidine + ipilimumab + nivolumab</td><td>182</td><td>II</td><td>Recruiting</td><td>NCT02397720</td></tr><tr><td> MDS</td><td>Azacitidine + nivolumab + ipilimumab</td><td>120</td><td>II</td><td>Recruiting</td><td>NCT02530463</td></tr><tr><td> MDS</td><td>Azacitidine + lirilumab + nivolumab</td><td>12</td><td>II</td><td>Completed</td><td>NCT02599649</td></tr><tr><td> High-risk MDS, AML</td><td>Azacitidine + sirolimus</td><td>74</td><td>II</td><td>Recruiting</td><td>NCT01869114</td></tr><tr><td> AML with IDH1 mutation</td><td>Azacitidine + AG-120</td><td>392</td><td>III</td><td>Recruiting</td><td>NCT03173248</td></tr><tr><td> Relapsed/refractory diffuse large B-cell lymphoma</td><td>Azacitidine + rituximab</td><td>27</td><td>II</td><td>Not yet recruiting</td><td>NCT03719989</td></tr><tr><td> Leukemia</td><td>Azacitidine + PKC412</td><td>54</td><td>I/II</td><td>Completed</td><td>NCT01202877</td></tr><tr><td> MDS</td><td>Azacitidine + sonidegib</td><td>78</td><td>I</td><td>Active, not recruiting</td><td>NCT02129101</td></tr><tr><td> MDS, AML and CMML</td><td>Azacitidine + PF-04449913</td><td>102</td><td>II</td><td>Recruiting</td><td>NCT02367456</td></tr><tr><td> MDS</td><td>Azacitidine + etanercept</td><td>32</td><td>I/II</td><td>Completed</td><td>NCT00118287</td></tr><tr><td> MDS, myeloproliferative neoplasm</td><td>Azacitidine + ruxolitinib Phosphate</td><td>123</td><td>II</td><td>Completed</td><td>NCT01787487</td></tr><tr><td> Relapsed or refractory AML, MDS</td><td>Azacitidine + quizartinib</td><td>72</td><td>I/II</td><td>Recruiting</td><td>NCT01892371</td></tr><tr><td> AML</td><td>Azacitidine vs fludarabine + cytarabine</td><td>289</td><td>III</td><td>Active, not recruiting</td><td>NCT02319135</td></tr><tr><td> AML, high-risk MDS</td><td>Azacitidine + cytarabine + tosedostat</td><td>96</td><td>I/II</td><td>Active, not recruiting</td><td>NCT01636609</td></tr><tr><td> Peripheral T-cell lymphoma</td><td>Azacitidine + CHOP</td><td>20</td><td>II</td><td>Recruiting</td><td>NCT03542266</td></tr><tr><td> AML</td><td>Azacitidine + intensive chemotherapy</td><td>720</td><td>III</td><td>Recruiting</td><td>NCT03416179</td></tr><tr><td> Advanced non-small-cell lung cancer</td><td>Azacitidine + paclitaxel</td><td>240</td><td>II</td><td>Active, not recruiting</td><td>NCT02250326</td></tr><tr><td colspan="6"><italic>Decitabine (5-aza-2</italic>′<italic>deoxycytidine)-based trials</italic></td></tr><tr><td> Refractory CML</td><td>Decitabine</td><td>40</td><td>II</td><td>Completed</td><td>NCT00042003</td></tr><tr><td> Metastatic papillary thyroid cancer or follicular thyroid cancer</td><td>Decitabine</td><td>12</td><td>II</td><td>Completed</td><td>NCT00085293</td></tr><tr><td> AML with TP53 mutation</td><td>Decitabine</td><td>60</td><td>II</td><td>Recruiting</td><td>NCT03063203</td></tr><tr><td> AML</td><td>Decitabine</td><td>546</td><td>II</td><td>Completed</td><td>NCT00416598</td></tr><tr><td> MDS</td><td>Decitabine</td><td>128</td><td>II</td><td>Completed</td><td>NCT00067808</td></tr><tr><td> Elderly patients with AML</td><td>Decitabine</td><td>238</td><td>II</td><td>Completed</td><td>NCT00866073</td></tr><tr><td> Advanced-stage MDS</td><td>Decitabine</td><td>160</td><td>III</td><td>Completed</td><td>NCT00043381</td></tr><tr><td> Relapse and refractory diffuse large B-cell lymphoma</td><td>Decitabine</td><td>60</td><td>IV</td><td>Recruiting</td><td>NCT03579082</td></tr><tr><td> Relapsed or refractory T lymphoblastic lymphoma</td><td>Decitabine</td><td>40</td><td>IV</td><td>Recruiting</td><td>NCT03558412</td></tr><tr><td> CML</td><td>Decitabine + imatinib mesylate</td><td>80</td><td>II</td><td>Completed</td><td>NCT00054431</td></tr><tr><td> High-risk MDS, AML</td><td>Decitabine + tosedostat</td><td>34</td><td>II</td><td>Completed</td><td>NCT01567059</td></tr><tr><td> Metastatic castration-resistant prostate cancer</td><td>Decitabine + enzalutamide</td><td>21</td><td>I/II</td><td>Not yet recruiting</td><td>NCT03709550</td></tr><tr><td> Peripheral T-cell lymphoma</td><td>Decitabine + CHOP</td><td>100</td><td>III</td><td>Not yet recruiting</td><td>NCT03553537</td></tr><tr><td> Relapsed FLT3-ITD-mutated AML, MDS</td><td>Decitabine + quizartinib</td><td>52</td><td>I/II</td><td>Recruiting</td><td>NCT03661307</td></tr><tr><td> AML</td><td>Decitabine + clofarabine</td><td>727</td><td>II</td><td>Active, not recruiting</td><td>NCT02085408</td></tr><tr><td> AML</td><td>Decitabine + ruxolitinib Phosphate</td><td>42</td><td>I/II</td><td>Recruiting</td><td>NCT02257138</td></tr><tr><td> AML</td><td>Decitabine + bortezomib</td><td>165</td><td>II</td><td>Active, not recruiting</td><td>NCT01420926</td></tr><tr><td> AML</td><td>Decitabine + cytarabine + daunorubicin hydrochloride</td><td>180</td><td>II</td><td>Active, not recruiting</td><td>NCT01627041</td></tr><tr><td colspan="6"><italic>Guadecitabine (SGI-110)-based trials</italic></td></tr><tr><td> AML</td><td>Guadecitabine</td><td>815</td><td>III</td><td>Completed</td><td>NCT02348489</td></tr><tr><td> Philadelphia-negative MDS</td><td>Guadecitabine</td><td>50</td><td>II</td><td>Recruiting</td><td>NCT03075826</td></tr><tr><td> High-risk MDS</td><td>Guadecitabine</td><td>103</td><td>II</td><td>Recruiting</td><td>NCT02131597</td></tr><tr><td> Advanced hepatocellular carcinoma (HCC)</td><td>Guadecitabine</td><td>51</td><td>II</td><td>Completed</td><td>NCT01752933</td></tr><tr><td> AML, MDS</td><td>Guadecitabine</td><td>401</td><td>I/II</td><td>Completed</td><td>NCT01261312</td></tr><tr><td> MDS, CMML</td><td>Guadecitabine</td><td>408</td><td>III</td><td>Recruiting</td><td>NCT02907359</td></tr><tr><td> AML, MDS</td><td>Guadecitabine + DLI</td><td>40</td><td>II</td><td>Not yet recruiting</td><td>NCT03454984</td></tr><tr><td> MDS relapsing post AlloSCT</td><td>Guadecitabine + DLI</td><td>90</td><td>II</td><td>Recruiting</td><td>NCT02684162</td></tr><tr><td> Refractory metastatic colorectal cancer</td><td>Guadecitabine + nivolumab</td><td>45</td><td>I/II</td><td>Not yet recruiting</td><td>NCT03576963</td></tr><tr><td> Recurrent ovarian, primary peritoneal, or fallopian tube cancer</td><td>Guadecitabine + Pembrolizumab</td><td>38</td><td>II</td><td>Recruiting</td><td>NCT02901899</td></tr><tr><td> Metastatic colorectal cancer</td><td>Guadecitabine + irinotecan</td><td>108</td><td>II</td><td>Active, not recruiting</td><td>NCT01896856</td></tr><tr><td>Advanced kidney cancer</td><td>Guadecitabine + durvalumab</td><td>58</td><td>I/II</td><td>Recruiting</td><td>NCT03308396</td></tr><tr><td> Refractory or resistant urothelial carcinoma</td><td>Guadecitabine + atezolizumab (anti-PD-L1 antibody)</td><td>53</td><td>II</td><td>Recruiting</td><td>NCT03179943</td></tr><tr><td> Advanced MDS CMML</td><td>Guadecitabine + atezolizumab</td><td>72</td><td>I/II</td><td>Recruiting</td><td>NCT02935361</td></tr><tr><td> Recurrent ovarian, fallopian tube, or primary peritoneal cancer</td><td>Guadecitabine + CDX-1401 Vaccine + atezolizumab</td><td>75</td><td>I/II</td><td>Recruiting</td><td>NCT03206047</td></tr><tr><td> Ovarian cancer</td><td>Guadecitabine + carboplatin</td><td>120</td><td>II</td><td>Completed</td><td>NCT01696032</td></tr><tr><td colspan="6"><italic>5-F-CdR-based trials</italic></td></tr><tr><td> Advanced cancer</td><td>5-Fluoro-2-deoxycytidine (FdCyd)</td><td>58</td><td>I</td><td>Completed</td><td>NCT00359606</td></tr><tr><td colspan="6"><italic>Hydralazine-based trials</italic></td></tr><tr><td> Ovarian cancer</td><td>Hydralazine + valproate</td><td>211</td><td>III</td><td>N/A</td><td>NCT00533299</td></tr><tr><td> Cervical cancer</td><td>Hydralazine + valproate</td><td>143</td><td>III</td><td>N/A</td><td>NCT00532818</td></tr><tr><td> Recurrent-persistent cervical cancer</td><td>Hydralazine + valproate</td><td>230</td><td>III</td><td>N/A</td><td>NCT02446652</td></tr><tr><td> Cervical cancer</td><td>Hydralazine + valproate + cisplatin</td><td>18</td><td>II</td><td>Completed</td><td>NCT00404326</td></tr><tr><td> Refractory solid tumors</td><td>Hydralazine + magnesium valproate</td><td>15</td><td>II</td><td>Completed</td><td>NCT00404508</td></tr></tbody></table><table-wrap-foot><p>Venetoclax, Bcl-2-selective inhibitor; Eltrombopag, c-mpl (TpoR) receptor agonist; APR-246, p53 agonist; DLI, donor leukocyte infusion; lenalidomide, derivative of thalidomide; sorafenib, multiple tyrosine kinase inhibitor; durvalumab, anti-PD-L1 monoclonal antibody; rigosertib, Ras mimetic; HAG regimen, homoharringtonine + cytarabine + G-CSF; lirilumab, anti-KIR monoclonal antibody; pembrolizumab, anti-PD-1 monoclonal antibody; lintuzumab, anti-CD33 monoclonal antibody; enasidenib, IDH2 inhibitor; avelumab, anti-PD-L1 monoclonal antibody; pevonedistat, NEDD8 inhibitor; nivolumab, anti-PD-1 monoclonal antibody; sirolimus, MTOR inhibitors; AG-120, IDH1 inhibitor; rituximab, anti-CD20 monoclonal antibody; PKC412, multitargeted protein kinase inhibitor; birinapant, SMAC mimetic antagonist; sonidegib, Hedgehog signaling pathway inhibitor; PF-04449913 (glasdegib), hedgehog signaling pathway inhibitor; etanercept, TNF inhibitor; ruxolitinib phosphate, JAK inhibitor; quizartinib, tyrosine kinase inhibitor; tosedostat, inhibitor of the M1 family of aminopeptidases; atezolizumab, anti-PD-L1 monoclonal antibody</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec18"><title>Inhibitors of histone modifications</title><p id="Par39">Compared with DNA methylation, histone modifications have been investigated in broader areas of diseases, including solid tumors, hematological malignancies, and even many inflammatory diseases (such as viral infection, diabetes and inflammatory lung diseases). During the process of gene silencing, lysine deacetylation and demethylation of H3K4 rather than demethylation of H3K9 or cytosine methylation might be the primary causative event.<sup><xref ref-type="bibr" rid="CR606">606</xref></sup> Therefore, histone modification plays an essential role in the regulation of gene expression, which also makes it a promising target for disease treatment. Clinical trials targeting histone acetylation and histone methylation are listed in Table <xref rid="Tab6" ref-type="table">6</xref> and Table <xref rid="Tab7" ref-type="table">7</xref>, respectively.<table-wrap id="Tab6"><label>Table 6</label><caption><p>Important ongoing clinical trials with histone acetylation-targeted therapies.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Condition</th><th>Design</th><th>Sample size</th><th>Phase</th><th>Current status</th><th>NCT</th></tr></thead><tbody><tr><td colspan="6"><bold>Anti-HDAC</bold></td></tr><tr><td colspan="6"><italic>Valproic acid-based trials</italic></td></tr><tr><td> Advanced thyroid cancers</td><td>Valproic acid</td><td>13</td><td>II</td><td>Completed</td><td>NCT01182285</td></tr><tr><td> Uveal melanoma</td><td>Valproic acid</td><td>150</td><td>II</td><td>Recruiting</td><td>NCT02068586</td></tr><tr><td> Pancreatic cancer</td><td>Valproic acid</td><td>20</td><td>II</td><td>N/A</td><td>NCT01333631</td></tr><tr><td> Non-Hodgkin lymphoma, Hodgkin lymphoma, CLL</td><td>Valproic acid</td><td>52</td><td>II</td><td>N/A</td><td>NCT01016990</td></tr><tr><td> Locally advanced head and neck squamous cell carcinoma</td><td>Valproic acid + platinum-based chemoradiation</td><td>14</td><td>II</td><td>Completed</td><td>NCT01695122</td></tr><tr><td> Non-small-cell lung cancer</td><td>Valproic acid + chemoradiotherapy</td><td>20</td><td>I/II</td><td>N/A</td><td>NCT01203735</td></tr><tr><td> Recurrent high-grade glioma</td><td>Valproic acid + sildenafil citrate + sorafenib tosylate</td><td>66</td><td>II</td><td>Recruiting</td><td>NCT01817751</td></tr><tr><td> Glioma</td><td>Valproic acid + levetiracetam</td><td>120</td><td>IV</td><td>Recruiting</td><td>NCT03048084</td></tr><tr><td> Virus-associated cancer</td><td>Valproic acid + avelumab</td><td>39</td><td>II</td><td>Recruiting</td><td>NCT03357757</td></tr><tr><td> Colorectal cancer</td><td>Valproic acid + radiation therapy</td><td>152</td><td>I/II</td><td>N/A</td><td>NCT01898104</td></tr><tr><td> Refractory or relapsing small-cell lung cancer</td><td>Valproic acid + doxorubicin, cyclophosphamide and vindesine</td><td>64</td><td>II</td><td>Completed</td><td>NCT00759824</td></tr><tr><td> High-grade gliomas, brain tumors</td><td>Valproic acid + temozolomide + radiation therapy</td><td>43</td><td>II</td><td>Completed</td><td>NCT00302159</td></tr><tr><td> High-grade gliomas or diffuse intrinsic pontine glioma</td><td>Valproic acid + radiation</td><td>38</td><td>II</td><td>Active, not recruiting</td><td>NCT00879437</td></tr><tr><td> Advanced malignant neoplasm</td><td>Valproic acid + bevacizumab + temsirolimus</td><td>216</td><td>I</td><td>Recruiting</td><td>NCT01552434</td></tr><tr><td> Malignant mesothelioma</td><td>Valproic acid + doxorubicin</td><td>45</td><td>II</td><td>Completed</td><td>NCT00634205</td></tr><tr><td> Diffuse large B-cell lymphoma</td><td>Valproic acid + rituximab + CHOP</td><td>50</td><td>I/II</td><td>Completed</td><td>NCT01622439</td></tr><tr><td colspan="6"><italic>Sodium phenylbutyrate-based trials</italic></td></tr><tr><td> Progressive or recurrent brain tumors</td><td>Phenylbutyrate</td><td>120</td><td>II</td><td>Completed</td><td>NCT00006450</td></tr><tr><td> Relapsed or refractory Epstein-Barr virus-positive cancer</td><td>Phenylbutyrate + valganciclovir</td><td>14</td><td>II</td><td>N/A</td><td>NCT00387530</td></tr><tr><td> Refractory or relapsed AML</td><td>Phenylbutyrate + dexamethasone + sargramostim</td><td>N/A</td><td>II</td><td>Completed</td><td>NCT00006240</td></tr><tr><td colspan="6"><italic>AN-9 (pivaloyloxymethyl butyrate)-based trials</italic></td></tr><tr><td> Advanced non-small-cell lung cancer</td><td>Pivanex + docetaxel</td><td>225</td><td>II</td><td>Completed</td><td>NCT00073385</td></tr><tr><td colspan="6"><italic>Phenylacetate-based trials</italic></td></tr><tr><td> Children with recurrent or progressive brain tumors</td><td>Phenylacetate</td><td>N/A</td><td>II</td><td></td><td>NCT00003241</td></tr><tr><td colspan="6"><italic>Vorinostat (SAHA)-based trials</italic></td></tr><tr><td> Advanced cancer</td><td>Vorinostat</td><td>143</td><td>I</td><td>Active, not recruiting</td><td>NCT01266057</td></tr><tr><td> BRAFV600-mutated advanced melanoma</td><td>Vorinostat</td><td>22</td><td>I/II</td><td>Recruiting</td><td>NCT02836548</td></tr><tr><td> Breast cancer</td><td>Vorinostat</td><td>49</td><td>I/II</td><td>N/A</td><td>NCT00416130</td></tr><tr><td> Advanced, metastatic soft tissue sarcoma</td><td>Vorinostat</td><td>40</td><td>II</td><td>Completed</td><td>NCT00918489</td></tr><tr><td> AML</td><td>Vorinostat</td><td>37</td><td>II</td><td>Completed</td><td>NCT00305773</td></tr><tr><td> Advanced non-small-cell lung cancer</td><td>Vorinostat</td><td>16</td><td>II</td><td>Completed</td><td>NCT00138203</td></tr><tr><td> Recurrent or persistent ovarian epithelial or primary peritoneal cavity cancer</td><td>Vorinostat</td><td>60</td><td>II</td><td>Completed</td><td>NCT00132067</td></tr><tr><td>advanced adenoid cystic carcinoma advanced thyroid cancer</td><td>Vorinostat</td><td>30</td><td>II</td><td>Completed</td><td>NCT01175980</td></tr><tr><td> Advanced thyroid cancer</td><td>Vorinostat</td><td>19</td><td>II</td><td>Completed</td><td>NCT00134043</td></tr><tr><td> Kidney cancer</td><td>Vorinostat</td><td>14</td><td>II</td><td>Completed</td><td>NCT00278395</td></tr><tr><td> Metastatic or unresectable melanoma</td><td>Vorinostat</td><td>32</td><td>II</td><td>Completed</td><td>NCT00121225</td></tr><tr><td> Low-grade non-Hodgkin lymphoma</td><td>Vorinostat</td><td>37</td><td>II</td><td>Completed</td><td>NCT00253630</td></tr><tr><td> Progressive glioblastoma multiforme</td><td>Vorinostat</td><td>103</td><td>II</td><td>Completed</td><td>NCT00238303</td></tr><tr><td> Progressive metastatic prostate cancer</td><td>Vorinostat</td><td>29</td><td>II</td><td>Completed</td><td>NCT00330161</td></tr><tr><td> Advanced cutaneous T-cell lymphoma</td><td>Vorinostat</td><td>74</td><td>II</td><td>Completed</td><td>NCT00091559</td></tr><tr><td> Advanced malignant pleural mesothelioma</td><td>Vorinostat</td><td>662</td><td>III</td><td>Completed</td><td>NCT00128102</td></tr><tr><td> Metastatic or recurrent gastric cancer</td><td>Vorinostat + capecitabine + cisplatin</td><td>45</td><td>I/II</td><td>Completed</td><td>NCT01045538</td></tr><tr><td> Breast cancer</td><td>Vorinostat + tamoxifen</td><td>43</td><td>II</td><td>Completed</td><td>NCT00365599</td></tr><tr><td> T-cell non-Hodgkin lymphoma</td><td>Vorinostat + CHOP</td><td>14</td><td>I/II</td><td>Completed</td><td>NCT00787527</td></tr><tr><td> Advanced non-small-cell lung cancer</td><td>Vorinostat + bortezomib</td><td>18</td><td>II</td><td>Completed</td><td>NCT00798720</td></tr><tr><td> Relapsed or refractory multiple myeloma</td><td>Vorinostat + bortezomib</td><td>143</td><td>II</td><td>Completed</td><td>NCT00773838</td></tr><tr><td> Recurrent glioblastoma multiforme</td><td>Vorinostat + bortezomib</td><td>44</td><td>II</td><td>Completed</td><td>NCT00641706</td></tr><tr><td> Advanced soft tissue sarcoma</td><td>Vorinostat + bortezomib</td><td>16</td><td>II</td><td>Completed</td><td>NCT00937495</td></tr><tr><td> Multiple myeloma</td><td>Vorinostat + bortezomib</td><td>637</td><td>III</td><td>Completed</td><td>NCT00773747</td></tr><tr><td> Unresectable or metastatic kidney cancer</td><td>Vorinostat + bevacizumab</td><td>37</td><td>I/II</td><td>Completed</td><td>NCT00324870</td></tr><tr><td> Glioblastoma multiforme</td><td>Vorinostat + temozolomide + radiation therapy</td><td>125</td><td>I/II</td><td>Active, not recruiting</td><td>NCT00731731</td></tr><tr><td> Diffuse intrinsic pontine glioma</td><td>Vorinostat + radiation therapy</td><td>80</td><td>I/II</td><td>Active, not recruiting</td><td>NCT01189266</td></tr><tr><td> Recurrent ovarian cancer</td><td>vorinostat + paclitaxel + carboplatin vorinostat + pembrolizumab</td><td>70</td><td>II</td><td>N/A</td><td>NCT00772798</td></tr><tr><td> Stage IV non-small-cell lung cancer (NSCLC)</td><td>Vorinostat + pembrolizumab</td><td>100</td><td>I/II</td><td>Recruiting</td><td>NCT02638090</td></tr><tr><td> CLL, small lymphocytic lymphoma</td><td>Vorinostat + fludarabine phosphate + cyclophosphamide + rituximab</td><td>40</td><td>I/II</td><td>Active, not recruiting</td><td>NCT00918723</td></tr><tr><td> Relapse/refractory AML</td><td>Vorinostat + temozolomide</td><td>23</td><td>II</td><td>Completed</td><td>NCT01550224</td></tr><tr><td> Stage II, III, or IV diffuse large B-cell lymphoma</td><td>Vorinostat + rituximab</td><td>83</td><td>I/II</td><td>Active, not recruiting</td><td>NCT00972478</td></tr><tr><td> Metastatic breast cancer</td><td>Vorinostat + paclitaxel + bevacizumab</td><td>54</td><td>I/II</td><td>Completed</td><td>NCT00368875</td></tr><tr><td> High-grade glioma</td><td>Vorinostat + radiation therapy</td><td>101</td><td>II/III</td><td>Completed</td><td>NCT01236560</td></tr><tr><td> High-risk MDS, AML</td><td>Vorinostat + idarubicin + cytarabine</td><td>106</td><td>II</td><td>Completed</td><td>NCT00656617</td></tr><tr><td> Colorectal cancer</td><td>Vorinostat + hydroxychloroquine</td><td>76</td><td>II</td><td>Recruiting</td><td>NCT02316340</td></tr><tr><td> Advanced non-small-cell lung cancer</td><td>Vorinostat + carboplatin + paclitaxel</td><td>94</td><td>II</td><td>Completed</td><td>NCT00481078</td></tr><tr><td> Metastatic colorectal cancer</td><td>Vorinostat + fluorouracil + leucovorin calcium</td><td>58</td><td>II</td><td>Completed</td><td>NCT00942266</td></tr><tr><td> Recurrent glioblastoma multiforme (GBM)</td><td>Vorinostat + isotretinoin + temozolomide</td><td>135</td><td>I/II</td><td>Active, not recruiting</td><td>NCT00555399</td></tr><tr><td> Breast cancer</td><td>Vorinostat + carboplatin + nab-paclitaxel</td><td>68</td><td>II</td><td>Completed</td><td>NCT00616967</td></tr><tr><td> Diffuse large B-cell non-Hodgkin lymphoma</td><td>Vorinostat + chemotherapy + rituximab</td><td>107</td><td>I/II</td><td>Active, not recruiting</td><td>NCT01193842</td></tr><tr><td> Advanced sarcoma</td><td>Vorinostat + gemcitabine + docetaxel</td><td>67</td><td>I/II</td><td>Recruiting</td><td>NCT01879085</td></tr><tr><td> AML</td><td>Vorinostat + cytarabine + daunorubicin Hydrochloride/idarubicin</td><td>754</td><td>III</td><td>Completed</td><td>NCT01802333</td></tr><tr><td> Neuroblastoma</td><td>Vorinostat + 131I-MIBG</td><td>105</td><td>II</td><td>Recruiting</td><td>NCT02035137</td></tr><tr><td> Multiple myeloma</td><td>Vorinostat + lenalidomide</td><td>4420</td><td>III</td><td>Active, not recruiting</td><td>NCT01554852</td></tr><tr><td> Relapsed/refractory cutaneous T-cell lymphoma (CTCL)</td><td>Vorinostat vs KW-0761</td><td>372</td><td>III</td><td>Active, not recruiting</td><td>NCT01728805</td></tr><tr><td colspan="6"><italic>TSA (Trichostatin A)-based trials</italic></td></tr><tr><td> Relapsed or refractory hematologic malignancies</td><td>Trichostatin A</td><td>42</td><td>I</td><td>Recruiting</td><td>NCT03838926</td></tr><tr><td colspan="6"><italic>Belinostat (PAHA, PXD101)-based trials</italic></td></tr><tr><td> Advanced solid tumors or lymphoma</td><td>Belinostat</td><td>121</td><td>I</td><td>Completed</td><td>NCT00413075</td></tr><tr><td> Relapsed or refractory peripheral T-cell lymphoma</td><td>Belinostat</td><td>129</td><td>II</td><td>Completed</td><td>NCT00865969</td></tr><tr><td> Liver cancer</td><td>Belinostat</td><td>54</td><td>I/II</td><td>Completed</td><td>NCT00321594</td></tr><tr><td> MDS</td><td>Belinostat</td><td>21</td><td>II</td><td>Completed</td><td>NCT00357162</td></tr><tr><td> Relapsed or refractory aggressive B-cell non-Hodgkin lymphoma</td><td>Belinostat</td><td>22</td><td>II</td><td>Completed</td><td>NCT00303953</td></tr><tr><td> Advanced multiple myeloma</td><td>Belinostat</td><td>25</td><td>II</td><td>Completed</td><td>NCT00131261</td></tr><tr><td> Solid tumors or hematological malignancies</td><td>Belinostat + warfarin</td><td>27</td><td>I</td><td>Completed</td><td>NCT01317927</td></tr><tr><td> Soft tissue sarcomas</td><td>Belinostat + doxorubicin</td><td>41</td><td>I/II</td><td>Completed</td><td>NCT00878800</td></tr><tr><td> Relapsed/refractory NHL</td><td>Belinostat + carfilzomib</td><td>19</td><td>I</td><td>Completed</td><td>NCT02142530</td></tr><tr><td> Relapsed or refractory AML, MDS</td><td>Belinostat + pevonedistat</td><td>45</td><td>I</td><td>Not yet recruiting</td><td>NCT03772925</td></tr><tr><td> Adult T-cell leukemia-lymphoma</td><td>Belinostat + zidovudine</td><td>20</td><td>II</td><td>Recruiting</td><td>NCT02737046</td></tr><tr><td> Recurrent ovarian epithelial cancer</td><td>Belinostat + carboplatin</td><td>29</td><td>II</td><td>Completed</td><td>NCT00993616</td></tr><tr><td> Stage IV non-small-cell lung cancer (NSCLC)</td><td>Belinostat + carboplatin + paclitaxel</td><td>23</td><td>I/II</td><td>Completed</td><td>NCT01310244</td></tr><tr><td> Ovarian cancer</td><td>Belinostat + carboplatin + paclitaxel</td><td>80</td><td>I/II</td><td>Completed</td><td>NCT00421889</td></tr><tr><td>Cancer of unknown primary site </td><td>Belinostat + carboplatin + paclitaxel</td><td>89</td><td>II</td><td>Completed</td><td>NCT00873119</td></tr><tr><td colspan="6"><italic>Entinostat (MS-275)-based trials</italic></td></tr><tr><td> Relapsed or refractory Hodgkin lymphoma</td><td>Entinostat</td><td>49</td><td>II</td><td>Completed</td><td>NCT00866333</td></tr><tr><td> MDS, AML, ALL</td><td>Entinostat</td><td>24</td><td>II</td><td>Completed</td><td>NCT00462605</td></tr><tr><td> Metastatic melanoma</td><td>Entinostat</td><td>28</td><td>II</td><td>Completed</td><td>NCT00185302</td></tr><tr><td> Advanced breast cancer</td><td>Entinostat</td><td>512</td><td>III</td><td>Recruiting</td><td>NCT03538171</td></tr><tr><td> Metastatic kidney cancer</td><td>Entinostat + aldesleukin</td><td>45</td><td>I/II</td><td>Active, not recruiting</td><td>NCT01038778</td></tr><tr><td> TN breast cancer</td><td>Entinostat + atezolizumab</td><td>88</td><td>I/II</td><td>Active, not recruiting</td><td>NCT02708680</td></tr><tr><td> Advanced epithelial ovarian cancer</td><td>Entinostat + avelumab</td><td>140</td><td>I/II</td><td>Active, not recruiting</td><td>NCT02915523</td></tr><tr><td> Metastatic colorectal cancer</td><td>Entinostat + regorafenib + hydroxychloroquine</td><td>44</td><td>I/II</td><td>Recruiting</td><td>NCT03215264</td></tr><tr><td> Advanced renal cell carcinoma</td><td>Entinostat + bevacizumab + atezolizumab</td><td>62</td><td>I/II</td><td>Recruiting</td><td>NCT03024437</td></tr><tr><td> Endometrioid endometrial cancer</td><td>Entinostat + medroxyprogesterone acetate</td><td>50</td><td>II</td><td>Active, not recruiting</td><td>NCT03018249</td></tr><tr><td> Renal cell carcinoma</td><td>Entinostat + IL-2</td><td>46</td><td>II</td><td>Recruiting</td><td>NCT03501381</td></tr><tr><td> NSCLC, melanoma, and colorectal cancer</td><td>Entinostat + pembrolizumab</td><td>202</td><td>I/II</td><td>Active, not recruiting</td><td>NCT02437136</td></tr><tr><td> Relapsed and refractory lymphomas</td><td>Entinostat + pembrolizumab</td><td>78</td><td>II</td><td>Recruiting</td><td>NCT03179930</td></tr><tr><td> Stage III/IV melanoma</td><td>Entinostat + pembrolizumab</td><td>14</td><td>II</td><td>Recruiting</td><td>NCT03765229</td></tr><tr><td> High-risk refractory malignancies</td><td>Entinostat + nivolumab</td><td>128</td><td>I/II</td><td>Not yet recruiting</td><td>NCT03838042</td></tr><tr><td> Metastatic cholangiocarcinoma and pancreatic adenocarcinoma</td><td>Entinostat + nivolumab</td><td>54</td><td>II</td><td>Recruiting</td><td>NCT03250273</td></tr><tr><td> Renal cell carcinoma</td><td>Entinostat + nivolumab + ipilimumab</td><td>53</td><td>II</td><td>Recruiting</td><td>NCT03552380</td></tr><tr><td> Advanced breast cancer</td><td>Entinostat + exemestane</td><td>130</td><td>II</td><td>Completed</td><td>NCT00676663</td></tr><tr><td> Breast cancer</td><td>Entinostat + exemestane</td><td>600</td><td>III</td><td>Active, not recruiting</td><td>NCT02115282</td></tr><tr><td> Advanced NSCLC</td><td>Entinostat + erlotinib</td><td>132</td><td>I/II</td><td>Completed</td><td>NCT00602030</td></tr><tr><td> Non-small-cell lung carcinoma</td><td>Entinostat + erlotinib</td><td>70</td><td>II</td><td>Completed</td><td>NCT00750698</td></tr><tr><td colspan="6"><italic>Panobinostat (LBH589)-based trials</italic></td></tr><tr><td> High-risk MDS, AML</td><td>Panobinostat</td><td>62</td><td>I/II</td><td>Active, not recruiting</td><td>NCT01451268</td></tr><tr><td> Advanced hematological malignancies</td><td>Panobinostat</td><td>175</td><td>I/II</td><td>Completed</td><td>NCT00621244</td></tr><tr><td> Metastatic thyroid cancer</td><td>Panobinostat</td><td>13</td><td>II</td><td>Completed</td><td>NCT01013597</td></tr><tr><td> Advanced soft tissue sarcoma</td><td>Panobinostat</td><td>53</td><td>II</td><td>Completed</td><td>NCT01136499</td></tr><tr><td> Refractory prostate cancer</td><td>Panobinostat</td><td>35</td><td>II</td><td>Completed</td><td>NCT00667862</td></tr><tr><td> Refractory clear cell renal carcinoma</td><td>Panobinostat</td><td>20</td><td>II</td><td>Completed</td><td>NCT00550277</td></tr><tr><td> Relapsed/refractory classical Hodgkin lymphoma</td><td>Panobinostat</td><td>129</td><td>II</td><td>Completed</td><td>NCT00742027</td></tr><tr><td> Refractory colorectal cancer</td><td>Panobinostat</td><td>29</td><td>II</td><td>Completed</td><td>NCT00690677</td></tr><tr><td> HER2-negative locally recurrent or metastatic breast cancer</td><td>Panobinostat</td><td>54</td><td>II</td><td>Completed</td><td>NCT00777049</td></tr><tr><td> Relapsed and bortezomib-refractory multiple myeloma</td><td>Panobinostat</td><td>55</td><td>II</td><td>Completed</td><td>NCT01083602</td></tr><tr><td> Relapsed or refractory non-Hodgkin lymphoma</td><td>Panobinostat</td><td>41</td><td>II</td><td>Active, not recruiting</td><td>NCT01261247</td></tr><tr><td> Refractory CML</td><td>Panobinostat</td><td>27</td><td>II/III</td><td>Completed</td><td>NCT00449761</td></tr><tr><td> Refractory/resistant cutaneous T-cell lymphoma</td><td>Panobinostat</td><td>9</td><td>II/III</td><td>Completed</td><td>NCT00490776</td></tr><tr><td> Refractory CML</td><td>Panobinostat</td><td>29</td><td>II/III</td><td>Completed</td><td>NCT00451035</td></tr><tr><td> Refractory cutaneous T-cell lymphoma</td><td>Panobinostat</td><td>139</td><td>II/III</td><td>Completed</td><td>NCT00425555</td></tr><tr><td> Hodgkin lymphoma (HL)</td><td>Panobinostat</td><td>41</td><td>III</td><td>Completed</td><td>NCT01034163</td></tr><tr><td> Relapsed/refractory multiple myeloma</td><td>Panobinostat + carfilzomib</td><td>80</td><td>I/II</td><td>Active, not recruiting</td><td>NCT01496118</td></tr><tr><td> Recurrent high-grade glioma</td><td>Panobinostat + bevacizumab</td><td>51</td><td>I/II</td><td>Completed</td><td>NCT00859222</td></tr><tr><td> Recurrent prostate cancer after castration</td><td>Panobinostat + bicalutamide</td><td>52</td><td>I/II</td><td>Completed</td><td>NCT00878436</td></tr><tr><td> AML</td><td>Panobinostat + idarubicin + cytarabine</td><td>46</td><td>I/II</td><td>Completed</td><td>NCT00840346</td></tr><tr><td> Diffuse large B-cell lymphoma (DLBCL)</td><td>Panobinostat + rituximab</td><td>42</td><td>II</td><td>N/A</td><td>NCT01238692</td></tr><tr><td> Relapsed and refractory lymphoma</td><td>Panobinostat + everolimus</td><td>31</td><td>I/II</td><td>Completed</td><td>NCT00967044</td></tr><tr><td> Gliomas</td><td>Panobinostat + everolimus</td><td>32</td><td>II</td><td>Recruiting</td><td>NCT03632317</td></tr><tr><td> Recurrent multiple myeloma, Non-Hodgkin lymphoma, or Hodgkin lymphoma</td><td>Panobinostat + everolimus</td><td>124</td><td>I/II</td><td>Active, not recruiting</td><td>NCT00918333</td></tr><tr><td> Relapsed/refractory peripheral T-cell lymphoma or NK/T-cell lymphoma</td><td>Panobinostat + bortezomib</td><td>25</td><td>II</td><td>Completed</td><td>NCT00901147</td></tr><tr><td> Relapsed or relapsed- and-refractory multiple myeloma</td><td>Panobinostat + bortezomib + dexamethasone</td><td>240</td><td>II</td><td>Recruiting</td><td>NCT02654990</td></tr><tr><td> Relapsed multiple myeloma</td><td>Panobinostat + bortezomib + dexamethasone</td><td>768</td><td>III</td><td>Completed</td><td>NCT01023308</td></tr><tr><td> Relapsed or refractory Hodgkin lymphoma</td><td>Panobinostat + lenalidomide</td><td>24</td><td>II</td><td>Completed</td><td>NCT01460940</td></tr><tr><td colspan="6"><italic>Mocetinostat (MGCD0103)-based trials</italic></td></tr><tr><td> Advanced solid tumors or non-Hodgkin lymphoma</td><td>Mocetinostat</td><td>42</td><td>I</td><td>Completed</td><td>NCT00323934</td></tr><tr><td> Refractory chronic lymphocytic leukemia</td><td>Mocetinostat</td><td>21</td><td>II</td><td>Completed</td><td>NCT00431873</td></tr><tr><td> Relapsed and refractory lymphoma</td><td>Mocetinostat</td><td>74</td><td>II</td><td>Completed</td><td>NCT00359086</td></tr><tr><td> Tumors</td><td>Mocetinostat + gemcitabine</td><td>47</td><td>I/II</td><td>Completed</td><td>NCT00372437</td></tr><tr><td> Relapsed or refractory Hodgkin lymphoma</td><td>Mocetinostat + brentuximab vedotin</td><td>7</td><td>I/II</td><td>Active, not recruiting</td><td>NCT02429375</td></tr><tr><td> Advanced solid tumors and NSCLC</td><td>Mocetinostat + durvalumab</td><td>119</td><td>I/II</td><td>Active, not recruiting</td><td>NCT02805660</td></tr><tr><td> Metastatic leiomyosarcoma</td><td>Mocetinostat + gemcitabine</td><td>20</td><td>II</td><td>Completed</td><td>NCT02303262</td></tr><tr><td> Non-small-cell lung cancer</td><td>Mocetinostat + glesatinib + sitravatinib + nivolumab</td><td>209</td><td>II</td><td>Recruiting</td><td>NCT02954991</td></tr><tr><td colspan="6"><italic>CI-994-based trials</italic></td></tr><tr><td> Advanced myeloma</td><td>CI-994</td><td>6</td><td>II</td><td>Completed</td><td>NCT00005624</td></tr><tr><td> Advanced pancreatic cancer</td><td>CI-994 + gemcitabine</td><td>N/A</td><td>II</td><td>Completed</td><td>NCT00004861</td></tr><tr><td> Advanced non-small-cell lung cancer</td><td>CI-994 + gemcitabine</td><td>N/A</td><td>III</td><td>Completed</td><td>NCT00005093</td></tr><tr><td colspan="6"><italic>Romidepsin (Depsipeptide, FR901228, FK228)-based trials</italic></td></tr><tr><td> Recurrent high-grade gliomas</td><td>Romidepsin</td><td>50</td><td>I/II</td><td>Completed</td><td>NCT00085540</td></tr><tr><td> Progressive or relapsed peripheral T-cell lymphoma</td><td>Romidepsin</td><td>131</td><td>II</td><td>Active, not recruiting</td><td>NCT00426764</td></tr><tr><td> Soft tissue sarcoma</td><td>Romidepsin</td><td>40</td><td>II</td><td>Completed</td><td>NCT00112463</td></tr><tr><td> Squamous cell carcinoma of the head and neck</td><td>Romidepsin</td><td>14</td><td>II</td><td>Completed</td><td>NCT00084682</td></tr><tr><td> Metastatic breast cancer</td><td>Romidepsin</td><td>37</td><td>II</td><td>Completed</td><td>NCT00098397</td></tr><tr><td> Relapsed small-cell lung cancer</td><td>Romidepsin</td><td>36</td><td>II</td><td>Completed</td><td>NCT00086827</td></tr><tr><td> Cutaneous T-cell lymphoma and peripheral T-cell lymphoma</td><td>Romidepsin</td><td>131</td><td>II</td><td>Completed</td><td>NCT00007345</td></tr><tr><td> Relapsed or refractory AML</td><td>Romidepsin</td><td>47</td><td>II</td><td>Completed</td><td>NCT00062075</td></tr><tr><td> Relapsed or refractory multiple myeloma</td><td>Romidepsin</td><td>50</td><td>II</td><td>Completed</td><td>NCT00066638</td></tr><tr><td> Relapsed or refractory non-Hodgkin lymphoma</td><td>Romidepsin</td><td>35</td><td>II</td><td>Completed</td><td>NCT00077194</td></tr><tr><td> Triple-negative breast cancer (TNBC)</td><td>Romidepsin + nivolumab + cisplatin</td><td>54</td><td>I/II</td><td>Recruiting</td><td>NCT02393794</td></tr><tr><td> Relapsed/refractory T-cell lymphoma</td><td>Romidepsin + tenalisib</td><td>42</td><td>I/II</td><td>Recruiting</td><td>NCT03770000</td></tr><tr><td> Lymphoid hematopoietic malignancy</td><td>Romidepsin + pembrolizumab</td><td>39</td><td>I/II</td><td>Recruiting</td><td>NCT03278782</td></tr><tr><td> Peripheral T-cell lymphoma (PTCL)</td><td>Romidepsin + ixazomib</td><td>48</td><td>I/II</td><td>Recruiting</td><td>NCT03547700</td></tr><tr><td> Relapsed/refractory lymphoid malignancies</td><td>Romidepsin + pralatrexate</td><td>93</td><td>I/II</td><td>Recruiting</td><td>NCT01947140</td></tr><tr><td> Peripheral T-cell lymphoma</td><td>Romidepsin + CHOP</td><td>421</td><td>III</td><td>Active, not recruiting</td><td>NCT01796002</td></tr><tr><td> Relapsed/refractory peripheral T-cell lymphoma</td><td>Romidepsin + gemcitabine</td><td>20</td><td>II</td><td>Completed</td><td>NCT01822886</td></tr><tr><td> Relapsed or refractory lymphomas and myeloma</td><td>Romidepsin + lenalidomide</td><td>62</td><td>I/II</td><td>Active, not recruiting</td><td>NCT01755975</td></tr><tr><td> Relapsed or refractory B- and T-cell lymphomas</td><td>Romidepsin + lenalidomide + carfilzomib</td><td>31</td><td>I/II</td><td>Active, not recruiting</td><td>NCT02341014</td></tr><tr><td> Peripheral T-cell lymphoma</td><td>Romidepsin + lenalidomide</td><td>35</td><td>II</td><td>Recruiting</td><td>NCT02232516</td></tr><tr><td colspan="6"><italic>Nicotinamide-based trials</italic></td></tr><tr><td> Skin cancer prevention</td><td>Nicotinamide</td><td>120</td><td>II</td><td>Recruiting</td><td>NCT03769285</td></tr><tr><td> Lung cancer</td><td>Nicotinamide</td><td>110</td><td>II/III</td><td>Active, not recruiting</td><td>NCT02416739</td></tr><tr><td> Bladder cancer</td><td>Niacinamide + radiation + carbogen</td><td>330</td><td>III</td><td>Completed</td><td>NCT00033436</td></tr><tr><td colspan="6"><bold>Inhibitors of sirtuins</bold></td></tr><tr><td colspan="6"><italic>Suramin-based trials</italic></td></tr><tr><td> Recurrent primary brain tumors</td><td>Suramin</td><td>N/A</td><td>II</td><td>Completed</td><td>NCT00002639</td></tr><tr><td> Hormone-refractory prostate cancer</td><td>Suramin</td><td>390</td><td>III</td><td>Completed</td><td>NCT00002723</td></tr><tr><td> Metastatic renal cell (kidney) cancer</td><td>Suramin + fluorouracil</td><td>36</td><td>I/II</td><td>Completed</td><td>NCT00083109</td></tr><tr><td> Advanced non-small-cell lung cancer</td><td>Suramin + docetaxel</td><td>80</td><td>II</td><td>N/A</td><td>NCT01671332</td></tr><tr><td> Stage IIIB-IV breast cancer</td><td>Suramin + paclitaxel</td><td>31</td><td>I/II</td><td>Completed</td><td>NCT00054028</td></tr><tr><td> Stage IIIB or IV non-small-cell lung cancer</td><td>Suramin + paclitaxel + carboplatin</td><td>82</td><td>II</td><td>Completed</td><td>NCT00006929</td></tr><tr><td> Poor-prognosis prostate carcinoma</td><td>Suramin + flutamide + leuprolide</td><td>70</td><td>II</td><td>Completed</td><td>NCT00001266</td></tr><tr><td> Prostate cancer</td><td>Suramin + flutamide + hydrocortisone</td><td>N/A</td><td>III</td><td>Completed</td><td>NCT00002881</td></tr><tr><td colspan="6"><bold>Inhibitors for HATs</bold></td></tr><tr><td colspan="6"><italic>CBP-targeted therapy</italic></td></tr><tr><td> Advanced myeloid malignancies</td><td>PRI-724</td><td>49</td><td>I/II</td><td>Completed</td><td>NCT01606579</td></tr><tr><td> Advanced pancreatic adenocarcinoma</td><td>PRI-724 + gemcitabine</td><td>20</td><td>I</td><td>Completed</td><td>NCT01764477</td></tr><tr><td colspan="6"><bold>BRD (BET) inhibitors</bold></td></tr><tr><td colspan="6"><italic>GSK525762 (I-BET762, molibresib)-based trials</italic></td></tr><tr><td> Relapsed, refractory hematologic malignancies</td><td>GSK525762</td><td>180</td><td>I</td><td>Recruiting</td><td>NCT01943851</td></tr><tr><td> NUT midline carcinoma (NMC) and other cancers</td><td>GSK525762</td><td>195</td><td>I</td><td>Active, not recruiting</td><td>NCT01587703</td></tr><tr><td> Castration-resistant prostate cancer</td><td>GSK525762 + androgen deprivation therapy</td><td>37</td><td>I</td><td>Active, not recruiting</td><td>NCT03150056</td></tr><tr><td> Advanced or metastatic breast cancer</td><td>GSK525762 + fulvestrant</td><td>294</td><td>II</td><td>Recruiting</td><td>NCT02964507</td></tr><tr><td colspan="6"><italic>CPI-0610-based trials</italic></td></tr><tr><td> Multiple myeloma</td><td>CPI-0610</td><td>30</td><td>I</td><td>Completed</td><td>NCT02157636</td></tr><tr><td> Progressive lymphoma</td><td>CPI-0610</td><td>64</td><td>I</td><td>Active, not recruiting</td><td>NCT01949883</td></tr><tr><td colspan="6"><italic>RO6870810 (TEN-010, RG6146, JQ2)-based trials</italic></td></tr><tr><td> AML, MDS</td><td>RO6870810</td><td>26</td><td>I</td><td>Completed</td><td>NCT02308761</td></tr><tr><td> Advanced solid tumors</td><td>RO6870810</td><td>52</td><td>I</td><td>Completed</td><td>NCT01987362</td></tr><tr><td> Advanced multiple myeloma</td><td>RO6870810</td><td>86</td><td>I</td><td>Recruiting</td><td>NCT03068351</td></tr><tr><td> Advanced ovarian cancer or triple-negative breast cancer</td><td>RO6870810 + atezolizumab</td><td>116</td><td>I</td><td>Suspended</td><td>NCT03292172</td></tr><tr><td> High-grade B-cell lymphoma</td><td>RO6870810 + venetoclax + rituximab</td><td>94</td><td>I</td><td>Recruiting</td><td>NCT03255096</td></tr><tr><td colspan="6"><italic>BAY1238097-based trials</italic></td></tr><tr><td> Neoplasms</td><td>BAY1238097</td><td>8</td><td>I</td><td>Terminated</td><td>NCT02369029</td></tr><tr><td colspan="6"><italic>MK8628 (OTX-015, birabresib)-based trials</italic></td></tr><tr><td> Advanced solid tumors</td><td>MK-8628</td><td>47</td><td>I</td><td>Completed</td><td>NCT02259114</td></tr><tr><td> Hematologic malignancies</td><td>MK-8628</td><td>9</td><td>I</td><td>Active, not recruiting</td><td>NCT02698189</td></tr><tr><td>Hematologic malignancies</td><td>MK-8628</td><td>141</td><td>I</td><td>Completed</td><td>NCT01713582</td></tr><tr><td colspan="6"><italic>FT-1101-based trials</italic></td></tr><tr><td> Relapsed or refractory hematologic malignancies</td><td>FT-1101</td><td>160</td><td>I</td><td>Recruiting</td><td>NCT02543879</td></tr><tr><td colspan="6"><italic>INCB057643-based trials</italic></td></tr><tr><td> Advanced malignancies</td><td>INCB057643</td><td>136</td><td>I/II</td><td>Active, not recruiting</td><td>NCT02711137</td></tr></tbody></table><table-wrap-foot><p>Lenalidomide, derivative of thalidomide; durvalumab, anti-PD-L1 monoclonal antibody; avelumab, anti-PD-L1 monoclonal antibody; bevacizumab, VEGF inhibitor; temsirolimus, mTOR inhibitor; rituximab, anti-CD20 monoclonal antibody; regorafenib, multikinase inhibitor; nivolumab, anti-PD-1 monoclonal antibody; sitravatinib, multiple tyrosine kinase inhibitor; tenalisib, inhibitor of PI3K; pembrolizumab, anti-PD-1 monoclonal antibody; atezolizumab, anti-PD-L1 monoclonal antibody</p></table-wrap-foot></table-wrap><table-wrap id="Tab7"><label>Table 7</label><caption><p>Important ongoing clinical trials with histone methylation-targeted therapies.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Condition</th><th>Design</th><th>Sample size</th><th>Phase</th><th>Current status</th><th>NCT</th></tr></thead><tbody><tr><td colspan="6"><bold>HMT inhibitor</bold></td></tr><tr><td colspan="6"> DOT1L-targeted therapy</td></tr><tr><td colspan="6"><italic>Pinometostat (EPZ-5676)-based trials</italic></td></tr><tr><td>Relapsed/refractory leukemias</td><td>Pinometostat</td><td>51</td><td>I</td><td>Completed</td><td>NCT01684150</td></tr><tr><td>Acute myeloid leukemia with MLL gene rearrangement</td><td>Pinometostat + standard chemotherapy</td><td>37</td><td>I/II</td><td>Recruiting</td><td>NCT03724084</td></tr><tr><td colspan="6"><italic>Tazemetostat (EPZ-6438)-based trials</italic></td></tr><tr><td> Diffuse large B-cell lymphoma</td><td>Tazemetostat</td><td>133</td><td>I/II</td><td>Suspended</td><td>NCT02889523</td></tr><tr><td> Advanced tumors/lymphomas</td><td>Tazemetostat</td><td>420</td><td>I/II</td><td>Recruiting</td><td>NCT01897571</td></tr><tr><td> Relapsed or refractory B-cell lymphoma with EZH2 gene mutation</td><td>Tazemetostat</td><td>21</td><td>II</td><td>Active, not recruiting</td><td>NCT03456726</td></tr><tr><td> Recurrent ovarian, primary peritoneal, or endometrial cancer</td><td>Tazemetostat</td><td>43</td><td>II</td><td>Recruiting</td><td>NCT03348631</td></tr><tr><td> Lymphoma, advanced solid tumors</td><td>Tazemetostat</td><td>300</td><td>II</td><td>Recruiting</td><td>NCT02875548</td></tr><tr><td> Malignant mesothelioma</td><td>Tazemetostat</td><td>67</td><td>II</td><td>Active, not recruiting</td><td>NCT02860286</td></tr><tr><td> INI1-negative tumors or relapsed/ refractory synovial sarcoma</td><td>Tazemetostat</td><td>250</td><td>II</td><td>Recruiting</td><td>NCT02601950</td></tr><tr><td> Relapsed/refractory lymphoma</td><td>Tazemetostat + atezolizumab</td><td>92</td><td>I</td><td>Active, not recruiting</td><td>NCT02220842</td></tr><tr><td> Advanced urothelial carcinoma</td><td>Tazemetostat + pembrolizumab</td><td>30</td><td>I/II</td><td>Not yet recruiting</td><td>NCT03854474</td></tr><tr><td colspan="6"><italic>GSK2816126-based trials</italic></td></tr><tr><td> Relapsed/refractory lymphomas, solid tumors and multiple myeloma</td><td>GSK2816126</td><td>41</td><td>I</td><td>Terminated</td><td>NCT02082977</td></tr><tr><td colspan="6"><italic>CPI-1205-based trials</italic></td></tr><tr><td> B-cell lymphomas</td><td>CPI-1205</td><td>41</td><td>I</td><td>Active, not recruiting</td><td>NCT02395601</td></tr><tr><td> Advanced solid tumors</td><td>CPI-1205</td><td>24</td><td>I/II</td><td>Active, not recruiting</td><td>NCT03525795</td></tr><tr><td> Castration-resistant prostate cancer</td><td>CPI-1205</td><td>242</td><td>I/II</td><td>Recruiting</td><td>NCT03480646</td></tr><tr><td colspan="6"><bold>Histone demethylase inhibitors</bold></td></tr><tr><td colspan="6"> LSD1-targeted therapy</td></tr><tr><td colspan="6"><italic>TCP-based trials</italic></td></tr><tr><td>AML and MDS</td><td>TCP</td><td>17</td><td>I</td><td>Active, not recruiting</td><td>NCT02273102</td></tr><tr><td>Relapsed or refractory AML</td><td>TCP</td><td>16</td><td>I/II</td><td>N/A</td><td>NCT02261779</td></tr><tr><td colspan="6"><italic>ORY-2001-based trials</italic></td></tr><tr><td> Mild to moderate Alzheimer's disease</td><td>ORY-2001</td><td>33</td><td>II</td><td>Not yet recruiting</td><td>NCT03867253</td></tr><tr><td colspan="6"><italic>GSK2879552-based trials</italic></td></tr><tr><td> High-risk MDS</td><td>GSK2879552 + azacitidine</td><td>74</td><td>II</td><td>Recruiting</td><td>NCT02929498</td></tr><tr><td colspan="6"><italic>4SC-202-based trials</italic></td></tr><tr><td> Advanced hematologic malignancy</td><td>4SC-202</td><td>36</td><td>I</td><td>Completed</td><td>NCT01344707</td></tr><tr><td> Malignant melanoma</td><td>4SC-202 + pembrolizumab</td><td>40</td><td>I/II</td><td>Recruiting</td><td>NCT03278665</td></tr></tbody></table><table-wrap-foot><p>Atezolizumab, anti-PD-L1 monoclonal antibody; pembrolizumab, anti-PD-1 monoclonal antibody</p></table-wrap-foot></table-wrap></p><sec id="Sec19"><title>Inhibitors for HATs and BETs</title><p id="Par40">Generally, there are two strategies for preventing aberrant histone acetylation, including altering interactions within the active sites within HATs or using mimetic products of enzymatic substrates. To date, many inhibitors targeting BRD proteins have been investigated in clinical trials, whereas there are no clinical trials investigating inhibitors for HATs.</p><p id="Par41">Bisubstrate inhibitors are selective inhibitors for PCAF, p300, and TIP60. They mimic two substrates of HATs: the cofactor acetyl coenzyme A (Ac-CoA) and a peptide resembling the lysine substrate.<sup><xref ref-type="bibr" rid="CR607">607</xref>,<xref ref-type="bibr" rid="CR608">608</xref></sup> However, due to their peptidic nature and size, they are not membrane-permeable and require the assistance of a delivery system. Based on inhibitory strategies for HATs, nonpeptide small molecular inhibitors have been developing as potential therapeutic agents. Several small molecule inhibitors are natural products, including garcinol, curcumin, and anacardic acid.<sup><xref ref-type="bibr" rid="CR609">609</xref>–<xref ref-type="bibr" rid="CR611">611</xref></sup> These natural HAT inhibitors lack selectivity between HATs and often have other targets. Therefore, structurally modified and synthetic compounds have been reported. Α-Methylene-g-butyrolactones are small molecular inhibitors of HATs with selectivity for either GCN5L2 or PCAF.<sup><xref ref-type="bibr" rid="CR612">612</xref></sup> Isothiazolone is another HAT inhibitor targeting p300 and PCAF.<sup><xref ref-type="bibr" rid="CR613">613</xref></sup> However, high reactivity towards thiolates limits the application of HAT inhibitors in biological systems. Other inhibitors of HATs, such as thiazide sulfonamide and C646, have been gradually identified and show promising effects in multiple cancers. Another strategy to inhibit HAT activity is to target protein–protein interactions between HATs and their interaction partners. This method is dependent on the function of the interactions rather than the acetylation activity of HATs. ICG-001 and PRI-724 are representatives of this kind of inhibitor. Appropriately applying HAT agonists is also important to correct aberrant acetylation during diseases. CTPB is derived from anacardic acid and selectively activates p300, resulting in gene transcription.<sup><xref ref-type="bibr" rid="CR609">609</xref></sup> TTK21 and SPV106 are two other agonists based on anacardic acid.</p><p id="Par42">Binding to BRDs and blocking acetylated lysine recognition is another mechanism that inhibits acetylation. JQ1 and I-BET762 are two representative inhibitors of the BET family. JQ1 is a cell-permeable small molecule and can competitively bind to BRD4 fusion oncoproteins, such as BRD4-NUT, resulting in cancer cell differentiation and apoptosis.<sup><xref ref-type="bibr" rid="CR614">614</xref></sup> Similarly, I-BET762 is also a synthetic mimic of and competes with BRD4.<sup><xref ref-type="bibr" rid="CR615">615</xref></sup> Other compounds, such as MS417, OTX-015, RVX-208, OXFBD, I-BET151, PFI-1, MS436, and XD14, are also BET inhibitors and have been well illustrated in other published papers.<sup><xref ref-type="bibr" rid="CR616">616</xref></sup> We will focus on the associations between these compounds and cancers. However, a number of non-BET proteins containing BRDs have attracted considerable attention. Many non-BET bromodomain inhibitors are based on a structure called the “WPF shelf” and a “gatekeeper” residue located at the start of the C helix.<sup><xref ref-type="bibr" rid="CR617">617</xref></sup> Several HATs have a BRD, such as Gcn5, PCFA, p300, and CBP. Inhibitors for CBP include MS2126, MS7972, ischemin, SGC-CBP30 and I-CBP112; optimized 1-(1H-indol-1-yl) ethanone derivatives have also shown promising results in inhibiting CBP and p300.<sup><xref ref-type="bibr" rid="CR618">618</xref></sup> BAZ2A/B bromodomain inhibitors include BAZ2-ICR and GSK2801. The quinolone-fused lactam LP99 was the first synthetic selective inhibitor for BRD7/9. I-BRD9 was identified by GlaxoSmithKline (GSK) and is a selective inhibitor of BRD9, which has more than 200-fold selectivity for BRD9 over BRD7 and 700-fold selectivity for BRD9 over BET family members.<sup><xref ref-type="bibr" rid="CR619">619</xref></sup> PFI-3 is a potential inhibitor of SMARCA4 and PB1 with a stronger affinity for the bromodomain of SMARCA4. However, Vangamudi et al. identified that the ATPase domain within SMARC4 bypassed the anticancer effects related to the bromodomain since PFI-3 did not inhibit cell proliferation.<sup><xref ref-type="bibr" rid="CR620">620</xref></sup> The BRPF1 (bromodomain and PHD finger-containing 1) protein is part of the BRPF family, which is a component of MYST family complexes. The inhibitors of BRPF1 include PFI-4, OF-1, and NI-57. 1,3-Dimethyl benzimidazolones were the first selective inhibitors of BRPF1. PFI-4 and OF-1 are two close analogs of 1,3-dimethyl benzimidazolone that have been identified by the Structural Genomics Consortium (SGC). Another BRPF1 inhibitor, NI-57, was discovered by the SGC based on a new quinolinone scaffold. Both NI-57 and OF-1 are thought to interact with BRPF1-3 as pan-BRPF bromodomain inhibitors. Based on the bromodomain contained within both TRIM24 (tripartite motif containing protein 24) and BRPF1, a dual inhibitor, IACS-9571, has been identified.<sup><xref ref-type="bibr" rid="CR621">621</xref></sup> Bromosporine is a panbromodomain inhibitor with good cellular activity, whereas in a recent study, researchers noticed that bromodomain inhibitors only targeted the BET family rather than other BRDs.<sup><xref ref-type="bibr" rid="CR622">622</xref></sup></p></sec><sec id="Sec20"><title>Inhibition of HDACs</title><p id="Par43">Given that multiple methods can regulate HDAC activity, the designation of HDAC inhibitors has its own advantages. In the 1970s, butyrate was found to induce the accumulation of acetylated histones in cancer cells, which is thought to be associated with the inhibition of deacetylation.<sup><xref ref-type="bibr" rid="CR623">623</xref></sup> Later, a natural extract, trichostatin A (TSA), was identified to inhibit the activity of partially purified HDACs and induce cancer cell differentiation and apoptosis.<sup><xref ref-type="bibr" rid="CR624">624</xref></sup> Gradually, more natural and synthetic compounds have been identified to inhibit histone deacetylation. A study reported that administration of HDAC inhibitors only regulates a small number of genes (1–2%) but induces an obvious and rapid decrease in <italic>c-Myc</italic> gene expression, which indicated that a restricted set of cellular genes was uniquely sensitive to regulation of histone acetylation.<sup><xref ref-type="bibr" rid="CR625">625</xref></sup> The combination of two HDAC inhibitors, SAHA and TSA, induced melanoma cell growth arrest by upregulating p21, p27 and NF-κB, and MG132 can enhance the effect of TSA.<sup><xref ref-type="bibr" rid="CR626">626</xref></sup> The inhibition of HDACs has been investigated in various cancers, with promising antitumor effects.<sup><xref ref-type="bibr" rid="CR627">627</xref>,<xref ref-type="bibr" rid="CR628">628</xref></sup> Based on the characteristics of their chemical structures, HDAC inhibitors can be divided into five groups: short-chain fatty acids, hydroxamic acids, benzamides, cyclic peptides, and hybrid molecules. In addition to those included in the five groups, some new synthetic compounds also act as inhibitors of HDACs.</p><p id="Par44">The short-chain fatty acid group contains sodium butyrate, valproic acid (VPA), sodium phenylbutyrate, and AN-9 (pivaloyloxymethyl butyrate). The effective concentration of butyrate is usually at the micromolar level. The group of hydroxamic acids includes more than ten members and is the best-studied class. Structural analyses of TSA and suberoylanilide hydroxamic acid (SAHA) show that they are noncompetitive inhibitors of HDACs since they share significant homology with class I and class II HDACs, which makes them mimics of the lysine substrates.<sup><xref ref-type="bibr" rid="CR629">629</xref></sup> In addition, they chelate the active zinc ion in a bidentate manner, which is crucial for enzymatic activity.<sup><xref ref-type="bibr" rid="CR624">624</xref></sup> Hexamethylene bisacetamide (HMBA) is a representative of the hybrid polar compounds (HPCs), whereas second-generation HPCs, such as oxamflatin, SAHA, suberic bishydroxamic acid (SBHA), and m-carboxycinnamic acid bishydroxamide (CBHA), have shown better inhibition of HDACs and anticancer effects than first-generation agents.<sup><xref ref-type="bibr" rid="CR630">630</xref></sup> Oxamflatin, scriptaid, and amide are analogs of TSA and show anticancer effects.<sup><xref ref-type="bibr" rid="CR631">631</xref>–<xref ref-type="bibr" rid="CR633">633</xref></sup> Benzamide inhibitors (MS-275, MGCD0103, and CI-994) are well-studied and show promising effects in the treatment of diseases, especially cancers. They inhibit histone deacetylation via binding to catalytic zinc ions within HDACs through carbonyl and amino groups. Inhibition of HDACs by benzamide inhibitors is thought to be reversible, but the bond may become tight and pseudoirreversible in a time-dependent manner.<sup><xref ref-type="bibr" rid="CR634">634</xref>,<xref ref-type="bibr" rid="CR635">635</xref></sup> However, benzamide inhibitors have less activity than members of the hydroxamate or cyclic peptide families, with an effective concentration around the micromolar range.<sup><xref ref-type="bibr" rid="CR636">636</xref></sup> Cyclic peptides can be further divided into two groups: cyclic tetrapeptide containing a 2-amino-8-oxo-9, 10-epoxy-decanoyl (AOE) moiety (HC-toxin, trapoxin) and cyclic peptides without the AOE moiety (apicidin and romidepsin). The epoxyketone group is essential for the inhibitors to bind to active zinc ions, but the epoxyketone-based bond is irreversible. Trapoxin is a fungal cyclic peptide and can irreversibly inhibit the activity of HDACs.<sup><xref ref-type="bibr" rid="CR637">637</xref></sup> Romidepsin, also known as FK228, most likely relies on one of the thiol groups to coordinate to the active site zinc ion.<sup><xref ref-type="bibr" rid="CR638">638</xref></sup> Garlic-associated derivatives, such as diallylsulfide and allylmercaptan, are capable of generating a thiol group that makes them potential inhibitors of HDACs.<sup><xref ref-type="bibr" rid="CR639">639</xref></sup> K-trap, an analog of trapoxin, and other derivatives, including 9-acyloxyapicidins and 9-hydroxy, have been under investigation. Depudecin is a natural epoxide derivative isolated from the fungus <italic>Alternaria brassicicola</italic>. Psammaplins is isolated from a marine sponge <italic>Pseudoceratina purpurea</italic>. These two natural extracts can inhibit the activity of HDACs.</p><p id="Par45">Early HDAC inhibitors were nonselective because of the high homology of the structure and catalytic mechanism of HDACs within each group. The first selective HDAC inhibitor was tubacin, which targets HDAC6 with increased tubulin acetylation but not histone acetylation.<sup><xref ref-type="bibr" rid="CR640">640</xref></sup> PCI-34051, a specific inhibitor of HDAC8, can induce caspase-dependent apoptosis in T-cell lymphoma but does not increase histone acetylation.<sup><xref ref-type="bibr" rid="CR641">641</xref></sup> Another benzamide inhibitor, SHI-1:2, shows HDAC1/HDAC2-specific inhibitory activity that is >100-fold more selective than that of other HDACs.<sup><xref ref-type="bibr" rid="CR642">642</xref></sup> New synthetic chemicals, such as SK7041 and splitomicin, selectively target class I HDACs and sir2-like family members, respectively. The same efforts have been made to develop inhibitors for sirtuins, the class III HDACs. Nicotinamide, a byproduct of the sirtuin enzyme reaction, is a widely used inhibitor of all sirtuins. Other compounds, such as cambinol, salermide, tenovin, EX-527, suramin, and AGK2, have also been reported as sirtuin inhibitors. Sirtuin inhibitors (such as nicotinamide) function via interactions with the NAD+ within the active site of sirtuins or through binding to acetyl-lysine.</p><p id="Par46">Of note, second-generation HDACs, including hydroxamic acids (vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat (LBH589)) and benzamides (entinostat (MS-275), tacedinaline (CI-994), and mocetinostat (MGCD0103)), are currently in clinical trials, and some of them have already been approved for disease treatment. The success of romidepsin in phase I clinical trials in cutaneous and peripheral T-cell lymphoma accelerated the development of HDAC inhibitors as anticancer drugs. In 2006, SAHA (vorinostat) was first approved by the US Food and Drug Administration (FDA) for the treatment of cancer, restricted to patients with cutaneous T-cell lymphoma (CTCL), as an HDAC inhibitor.<sup><xref ref-type="bibr" rid="CR643">643</xref></sup> Romidepsin (Istodax) was the second approved HDAC inhibitor, which was approved in 2009. Three members of the benzamide family have also shown clinical significance in anticancer drug development. Belinostat (Beleodaq, previously known as PXD101) was approved in 2014 by the US FDA and European Medicines Agency to treat peripheral T-cell lymphoma. Another HDAC inhibitor, panobinostat, is a nonselective HDAC (pan-HDAC). It has shown promising effects in anticancer treatments; therefore, the FDA accelerated its approval for the treatment of patients with multiple myeloma. Intriguing, as we mentioned before, truncating mutations in HDAC2 have been found in sporadic carcinomas and colorectal cancer and result in resistance to traditional HDAC inhibitors.<sup><xref ref-type="bibr" rid="CR644">644</xref></sup> Mutations in other HDACs also exist; therefore, screening of these mutations in cancer can improve the efficacy of HDAC inhibitors.</p></sec><sec id="Sec21"><title>Inhibitor of HMTs and HDMTs</title><p id="Par47">EPZ004777 was the first identified selective inhibitor of DOT1L and selectively kills MLL-translocated cells over those without MLL translocation.<sup><xref ref-type="bibr" rid="CR645">645</xref></sup> However, due to its poor pharmacokinetic properties, a second generation of EPZ004777, EPZ-5767, was developed with a cyclobutyl ring replacing the ribose moiety.<sup><xref ref-type="bibr" rid="CR646">646</xref></sup> EPZ-5767 also shows synergistic effects with cytarabine, daunorubicin, and the DNMT inhibitor azacitidine in treatments for ALL with MLL translocation. EPZ-5767, though still showing low oral bioavailability, has been investigated in clinical trials for the treatment of leukemia with MLL rearrangement.<sup><xref ref-type="bibr" rid="CR647">647</xref></sup> There are several inhibitors of EZH2. 3-Deazaneplanocin A (DZNep), a derivative of the antibiotic neplanocin-A, is one of the most studied compounds. In fact, DZNep is a SAH-hydrolase inhibitor and decreases EZH2 expression via upregulation of SAH, which leads to degradation of PRC2 in a feedback inhibition mechanism.<sup><xref ref-type="bibr" rid="CR648">648</xref>,<xref ref-type="bibr" rid="CR649">649</xref></sup> Another kind of inhibitor is SAM competitive inhibitors. SAM is responsible for the methyl moiety of KMTs. EI1, a small molecular inhibitor of EZH2, inhibits EZH2 activity by directly binding to EZH2 and competing with SAM.<sup><xref ref-type="bibr" rid="CR650">650</xref></sup> GSK343 and GSK126 are two other SAM competitive inhibitors that have been investigated in clinical trials.<sup><xref ref-type="bibr" rid="CR651">651</xref>,<xref ref-type="bibr" rid="CR652">652</xref></sup> EPZ005687, a potent inhibitor of EZH2, significantly reduces H3K27 methylation in lymphoma cells with point mutations at the Tyr641 and Ala677 residues of EZH2 without obvious effects on the proliferation of wild-type cells.<sup><xref ref-type="bibr" rid="CR653">653</xref></sup> EPZ-6438, which shows similar effects and superior oral bioavailability, was developed next.<sup><xref ref-type="bibr" rid="CR654">654</xref></sup> CPI-1205 is a novel inhibitor of EZH2 that belongs to the pyridone family.</p><p id="Par48">Tranylcypromine (TCP) is an approved drug for depression due to its ability to inhibit monoamine oxidase (MAO) activity. The structures of LSD enzymes and MAOs share many similarities. Therefore, the side effects of TCP as an HDMT inhibitor, including orthostatic hypotension, dizziness, and drowsiness,<sup><xref ref-type="bibr" rid="CR655">655</xref></sup> are mostly caused by targeting of MAO. Administration of TCP in MLL-AF9 leukemia promotes tumor cell differentiation and apoptosis.<sup><xref ref-type="bibr" rid="CR656">656</xref></sup> TCP is also capable of resensitizing non-acute promyelocytic leukemia (APL) AML cells to all-trans retinoic acid (ATRA) treatment via increasing H3K4me2 and the expression of myeloid-differentiation-associated genes.<sup><xref ref-type="bibr" rid="CR657">657</xref></sup> Several derivatives of TCP have been developed to achieve better bioavailability and selectivity, including OG-002, RN-1, SP2509, and GSK690.<sup><xref ref-type="bibr" rid="CR658">658</xref>–<xref ref-type="bibr" rid="CR660">660</xref></sup> Another LSD1 selective inhibitor, ORY-1001, can also promote the differentiation of leukemia cell lines, especially cells with translocations in MLL, and has good oral bioavailability.<sup><xref ref-type="bibr" rid="CR661">661</xref></sup> To date, three LSD1 inhibitors, including TCP, ORY-1001, and GSK2879552, have been under investigation in clinical trials for the treatment of cancer patients. Daminozide (N-(dimethylamino) succinamic acid, 160 Da), a plant growth regulator, selectively inhibits KDM2/7 by chelating the active site metal.<sup><xref ref-type="bibr" rid="CR662">662</xref></sup> Daminozide and siRNA can similarly downregulate KDM7 expression and then regulate tumor-repopulating cells via demethylation of H3K9.<sup><xref ref-type="bibr" rid="CR663">663</xref></sup> GSK-J1 was the first identified KDM6 inhibitor with restricted cellular permeability, which resulted from its highly polar structure. Its ethyl ester, GSK-J4, possesses an improved ability to enter cells.<sup><xref ref-type="bibr" rid="CR664">664</xref></sup> However, scientists have found that GSK-J1 shows compatible selectivity for the KDM6 and KDM5 families and that GSK-J4 is also a potential inhibitor for KDM5B and KDM4C.<sup><xref ref-type="bibr" rid="CR665">665</xref></sup> EPT-103182, a selective inhibitor of KDM5B, has shown promising results in terms of antiproliferative effects in hematological and solid cancer cells. KDM8 and JMJD6 share homology and can be inhibited by a broad spectrum inhibitor, NOG.<sup><xref ref-type="bibr" rid="CR661">661</xref></sup></p><p id="Par49">Specific inhibitors usually have similar selectivity to closely related homologs within a group, and even across different groups, which needs to be taken into consideration when using compounds that are not highly selective.</p></sec></sec><sec id="Sec22"><title>Combined therapy</title><p id="Par50">Epigenetic regulation during tumorigenesis is complicated and involves multiple steps. Therefore, the combination of two or more therapies targeting various epigenetic events seems helpful. This combination synergistically inhibits the expression of tumor-growth-promoting genes and promotes the reexpression of tumor suppressor genes. 4SC-202 is a small molecular drug with dual effects that can inhibit HDAC1/2/3 and LSD1 with similar low micromolar potency. This drug is under clinical investigation. Other studies have administered two or more kinds of epigenetic drugs for anticancer therapy. Relevant clinical trials are listed in Table <xref rid="Tab8" ref-type="table">8</xref>.<table-wrap id="Tab8"><label>Table 8</label><caption><p>Important ongoing clinical trials with combination therapies including DNA methylation and histone modification.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Condition</th><th>Design</th><th>Sample size</th><th>Phase</th><th>Current status</th><th>NCT</th></tr></thead><tbody><tr><td colspan="6"><italic>Histone acetylation inhibitor</italic> + <italic>DNA methylation inhibitor</italic></td></tr><tr><td> Solid tumors, hematologic malignancies</td><td>Azacitidine + pracinostat</td><td>85</td><td>I</td><td>Completed</td><td>NCT00741234</td></tr><tr><td> MDS</td><td>Azacitidine + pracinostat</td><td>102</td><td>II</td><td>Completed</td><td>NCT01873703</td></tr><tr><td> High-risk MDS</td><td>Azacitidine + pracinostat</td><td>60</td><td>II</td><td>Active, not recruiting</td><td>NCT03151304</td></tr><tr><td> AML</td><td>Azacitidine + pracinostat</td><td>500</td><td>III</td><td>Recruiting</td><td>NCT03151408</td></tr><tr><td> MDS</td><td>Azacitidine + mocetinostat</td><td>18</td><td>I/II</td><td>Completed</td><td>NCT02018926</td></tr><tr><td> High-risk MDS, AML</td><td>Azacitidine + mocetinostat</td><td>66</td><td>I/II</td><td>Completed</td><td>NCT00324220</td></tr><tr><td> Advanced cancers</td><td>Azacitidine + valproic acid</td><td>69</td><td>I</td><td>Completed</td><td>NCT00496444</td></tr><tr><td> AML, MDS</td><td>Azacitidine + valproic acid</td><td>50</td><td>II</td><td>Recruiting</td><td>NCT02124174</td></tr><tr><td> Intermediate II and high-risk MDS</td><td>Azacitidine + valproic acid</td><td>62</td><td>II</td><td>Completed</td><td>NCT00439673</td></tr><tr><td> AML, MDS</td><td>Azacitidine + valproic acid + ATRA</td><td>34</td><td>II</td><td>Completed</td><td>NCT00326170</td></tr><tr><td> High-risk MDS</td><td>Azacitidine + valproic acid/lenalidomide/idarubicin</td><td>320</td><td>II</td><td>Active, not recruiting</td><td>NCT01342692</td></tr><tr><td> Higher-risk MDS, CML</td><td>Azacitidine + vorinostat</td><td>282</td><td>II</td><td>Active, not recruiting</td><td>NCT01522976</td></tr><tr><td> AML, high-risk MDS</td><td>Azacitidine + vorinostat</td><td>260</td><td>II</td><td>Active, not recruiting</td><td>NCT01617226</td></tr><tr><td> AML, MDS</td><td>Azacitidine + vorinostat</td><td>135</td><td>I/II</td><td>Active, not recruiting</td><td>NCT00392353</td></tr><tr><td> Relapsed/refractory lymphoma</td><td>Azacitidine + vorinostat</td><td>17</td><td>I/II</td><td>Completed</td><td>NCT01120834</td></tr><tr><td> Relapsed/refractory lymphoid malignancies</td><td>Azacitidine + romidepsin</td><td>60</td><td>I/II</td><td>Recruiting</td><td>NCT01998035</td></tr><tr><td> Relapsed or refractory AITL</td><td>Azacitidine + romidepsin + bendamustine + gemcitabine</td><td>86</td><td>III</td><td>Recruiting</td><td>NCT03593018</td></tr><tr><td> Lymphoma</td><td>Azacitidine + romidepsin + durvalumab + pralatrexate</td><td>148</td><td>I/II</td><td>Recruiting</td><td>NCT03161223</td></tr><tr><td> Advanced non-small-cell lung cancer</td><td>Azacitidine + entinostat</td><td>162</td><td>II</td><td>Completed</td><td>NCT00387465</td></tr><tr><td> AML</td><td>Azacitidine + entinostat</td><td>108</td><td>II</td><td>Recruiting</td><td>NCT01305499</td></tr><tr><td> Advanced breast cancer</td><td>Azacitidine + entinostat</td><td>58</td><td>II</td><td>Active, not recruiting</td><td>NCT01349959</td></tr><tr><td> AML, MDS, CML</td><td>Azacitidine + entinostat</td><td>197</td><td>II</td><td>Completed</td><td>NCT00313586</td></tr><tr><td> Metastatic colorectal cancer</td><td>Azacitidine + entinostat</td><td>47</td><td>II</td><td>Completed</td><td>NCT01105377</td></tr><tr><td> Non-small-cell lung cancer</td><td>Azacitidine + entinostat + nivolumab</td><td>120</td><td>II</td><td>Recruiting</td><td>NCT01928576</td></tr><tr><td> Leukemia, lung cancer, lymphoma, multiple myeloma, prostate cancer</td><td>Azacitidine + phenylbutyrate</td><td>N/A</td><td>II</td><td>Completed</td><td>NCT00006019</td></tr><tr><td> AML with 11q23 rearrangement</td><td>Azacitidine + pinometostat</td><td>36</td><td>I/II</td><td>Not yet recruiting</td><td>NCT03701295</td></tr><tr><td> High-risk MDS</td><td>Azacitidine + GSK2879552</td><td>74</td><td>II</td><td>Recruiting</td><td>NCT02929498</td></tr><tr><td> AML, MDS</td><td>Decitabine + valproic acid</td><td>153</td><td>II</td><td>Completed</td><td>NCT00414310</td></tr><tr><td> Relapsed/refractory MDS, leukemia</td><td>Decitabine + valproic acid</td><td>54</td><td>I/II</td><td>Completed</td><td>NCT00075010</td></tr><tr><td> AML</td><td>Decitabine + valproic acid</td><td>204</td><td>II</td><td>Completed</td><td>NCT00867672</td></tr><tr><td> AML, MDS</td><td>Decitabine + vorinostat</td><td>71</td><td>I</td><td>Completed</td><td>NCT00479232</td></tr><tr><td> AML, MDS</td><td>Decitabine + panobinostat</td><td>52</td><td>I/II</td><td>Completed</td><td>NCT00691938</td></tr><tr><td> Relapsed or refractory leukemia and MDS</td><td>Decitabine + romidepsin</td><td>36</td><td>I</td><td>Completed</td><td>NCT00114257</td></tr><tr><td> Advanced lung cancer</td><td>Guadecitabine + mocetinostat + pembrolizumab</td><td>40</td><td>I</td><td>Recruiting</td><td>NCT03220477</td></tr><tr><td> Lung cancer</td><td>Hydralazine + valproic acid</td><td>29</td><td>I</td><td>Completed</td><td>NCT00996060</td></tr><tr><td> Metastatic cervical cancer</td><td>Hydralazine + valproate</td><td>143</td><td>III</td><td>N/A</td><td>NCT00532818</td></tr><tr><td> Ovarian cancer</td><td>Hydralazine + valproate</td><td>211</td><td>III</td><td>N/A</td><td>NCT00533299</td></tr><tr><td> Cervical cancer</td><td>Hydralazine + valproate + cisplatin chemoradiation</td><td>18</td><td>II</td><td>Completed</td><td>NCT00404326</td></tr><tr><td> Refractory solid tumors</td><td>Hydralazine + magnesium valproate</td><td>15</td><td>II</td><td>Completed</td><td>NCT00404508</td></tr><tr><td colspan="6"><italic>BET inhibitor</italic> + <italic>DNA methylation inhibitor</italic></td></tr><tr><td> Relapsed or refractory hematologic malignancies</td><td>FT-1101 + azacitidine</td><td>160</td><td>I</td><td>Recruiting</td><td>NCT02543879</td></tr><tr><td> AML, MDS</td><td>GSK3326595 (selective inhibitor of protein arginine methyltransferase 5 (PRMT5)) vs azacitidine</td><td>302</td><td>I/II</td><td>Recruiting</td><td>NCT03614728</td></tr></tbody></table><table-wrap-foot><p>Pembrolizumab, anti-PD-1 monoclonal antibody; lenalidomide, derivative of thalidomide; durvalumab, anti-PD-L1 monoclonal antibody; nivolumab, anti-PD-1 monoclonal antibody</p></table-wrap-foot></table-wrap></p></sec></sec><sec id="Sec23" sec-type="conclusion"><title>Conclusion</title><p id="Par51">Although more specific mechanisms need to be investigated, it is well accepted that epigenetic events are important in normal biological processes as well as in tumorigenesis and that the epigenetic status is usually widely altered during cancer initiation. This makes epigenome-targeted therapy a promising strategy for the treatment of cancer. Based on the complexity of cancer, epigenetic alterations have influenced multiple aspects in cancer, such as the expression of oncogenes and tumor suppressor genes and signal transduction, resulting in enhanced cancer growth, invasion and metastasis. Although epigenetic therapy has a rational and profound basis in theory, some problems remain to be discussed and solved. The first and most important is the problem of selectivity. Epigenetic events are ubiquitously distributed across normal and cancer cells. In fact, some cancers depend on certain epigenetic alterations and can be sensitive to this regulation, whereas under usual regulation, normal cells have the ability to compensate for these epigenetic changes. Therefore, the priority is to determine the most important epigenetic alterations for different cancers. The second problem extends from the first problem. Thus far, epigenetic therapy has obtained impressive results in hematological malignancies but not in solid tumors. The properties of hematological malignant cells and solid tumor cells are different. However, researchers have still investigated the appropriate strategies for solid tumors. Since epigenetic alterations have effects on the sensitivity of small molecule targeted therapy and chemotherapy or radiotherapy, epigenetic-targeted therapy seems to be an important adjunctive therapy. The combination of epigenetic therapy and immunotherapy has also been investigated in preclinical and clinical trials.</p><p id="Par52">Based on the achievements obtained, epigenetic-targeted therapy is a promising strategy for anticancer treatment. Epigenomes in cancer are related to many aspects during cancer initiation. A better understanding of the specific mechanisms underlying those alterations in different cancers is necessary. Meanwhile, optimized treatment options, including a variety of combinations, still remain to be discovered.</p></sec></body><back><fn-group><fn><p>These authors contributed equally: Yuan Cheng, Cai He</p></fn></fn-group><ack><title>Acknowledgements</title><p>This work is supported by the Excellent Youth Foundation of Sichuan Scientific Committee Grant in China (No. 2019JDJQ0008), the National Major Scientific and Technological Special Project for “Significant New Drugs Development” of China (No. 2018ZX09733001) , and the National Key Research and Development Program of China (No. 2016YFA0201402). This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.</p></ack><notes notes-type="COI-statement"><title>Conflict of interest</title><p id="Par53">The authors declare that they have no conflict of interest.</p></notes><ref-list id="Bib1"><title>References</title><ref id="CR1"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Waddington</surname><given-names>CH</given-names></name></person-group><article-title>The epigenotype</article-title><source>Int J. 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