CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
Identifieur interne : 001041 ( Ncbi/Merge ); précédent : 001040; suivant : 001042CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
Auteurs : Zhen Zhang [République populaire de Chine] ; Jianjun Li [République populaire de Chine] ; Yang Ou [République populaire de Chine] ; Guang Yang [République populaire de Chine] ; Kaiyuan Deng [République populaire de Chine] ; Qiong Wang [République populaire de Chine] ; Zhaoyang Wang [République populaire de Chine] ; Wenhao Wang [République populaire de Chine] ; Quansheng Zhang [République populaire de Chine] ; Hang Wang [République populaire de Chine] ; Wei Sun [République populaire de Chine] ; Peiqing Sun [États-Unis] ; Shuang Yang [République populaire de Chine]Source :
- Signal Transduction and Targeted Therapy [ 2095-9907 ] ; 2020.
Abstract
Tumor metastasis is the most common cause of cancer-related deaths, yet it remains poorly understood. The transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) is involved in the epithelial-to-mesenchymal transition (EMT) and plays a pivotal role in tumor metastasis. However, the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown. Herein, we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo. Mechanistically, we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6. The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1. Moreover, we found a strong positive correlation between the expression of
Url:
DOI: 10.1038/s41392-020-0118-x
PubMed: 32195004
PubMed Central: 7064488
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7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Qiong" sort="Wang, Qiong" uniqKey="Wang Q" first="Qiong" last="Wang">Qiong Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Zhaoyang" sort="Wang, Zhaoyang" uniqKey="Wang Z" first="Zhaoyang" last="Wang">Zhaoyang Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Wenhao" sort="Wang, Wenhao" uniqKey="Wang W" first="Wenhao" last="Wang">Wenhao Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Quansheng" sort="Zhang, Quansheng" uniqKey="Zhang Q" first="Quansheng" last="Zhang">Quansheng Zhang</name><affiliation wicri:level="1"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0605 6814</institution-id><institution-id institution-id-type="GRID">grid.417024.4</institution-id><institution>Tianjin Key Laboratory of Organ Transplantation,</institution><institution>Tianjin First Center Hospital,</institution></institution-wrap>Tianjin, 300192 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Hang" sort="Wang, Hang" uniqKey="Wang H" first="Hang" last="Wang">Hang Wang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Sun, Wei" sort="Sun, Wei" uniqKey="Sun W" first="Wei" last="Sun">Wei Sun</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></affiliation></author><author><name sortKey="Sun, Peiqing" sort="Sun, Peiqing" uniqKey="Sun P" first="Peiqing" last="Sun">Peiqing Sun</name><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2185 3318</institution-id><institution-id institution-id-type="GRID">grid.241167.7</institution-id><institution>Department of Cancer Biology,</institution><institution>Wake Forest University School of Medicine,</institution></institution-wrap>Winston-Salem, NC 27157 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Winston-Salem</wicri:cityArea></affiliation></author><author><name sortKey="Yang, Shuang" sort="Yang, Shuang" uniqKey="Yang S" first="Shuang" last="Yang">Shuang Yang</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Tianjin</wicri:regionArea></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="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Tumor metastasis is the most common cause of cancer-related deaths, yet it remains poorly understood. The transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) is involved in the epithelial-to-mesenchymal transition (EMT) and plays a pivotal role in tumor metastasis. However, the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown. Herein, we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo. Mechanistically, we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6. The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1. Moreover, we found a strong positive correlation between the expression of <italic>p</italic>-RB (an indicator of CDK4/6 activity), <italic>p</italic>-USP51 and ZEB1 in metastatic human breast cancer samples. Notably, the high expression of <italic>p</italic>-RB, <italic>p</italic>-USP51, and ZEB1 was significantly correlated with a poor clinical outcome. Taken together, our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Turajlic, S" uniqKey="Turajlic S">S Turajlic</name></author><author><name sortKey="Swanton, C" uniqKey="Swanton C">C Swanton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nan, Xiang" uniqKey="Nan X">Xiang Nan</name></author><author><name sortKey="Wang, Jiang" uniqKey="Wang J">Jiang Wang</name></author><author><name sortKey="Liu, Haowen Nikola" uniqKey="Liu H">Haowen Nikola Liu</name></author><author><name sortKey="Wong, Stephen T C" uniqKey="Wong S">Stephen T.C. 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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">32195004</article-id><article-id pub-id-type="pmc">7064488</article-id><article-id pub-id-type="publisher-id">118</article-id><article-id pub-id-type="doi">10.1038/s41392-020-0118-x</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Zhen</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Jianjun</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ou</surname><given-names>Yang</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Guang</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Deng</surname><given-names>Kaiyuan</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Qiong</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Zhaoyang</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Wenhao</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Quansheng</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Hang</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Peiqing</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Yang</surname><given-names>Shuang</given-names></name><address><email>yangshuang@nankai.edu.cn</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation,</institution><institution>Medical College of Nankai University,</institution></institution-wrap>Tianjin, 300071 China</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9878 7032</institution-id><institution-id institution-id-type="GRID">grid.216938.7</institution-id><institution>College of Pharmacy,</institution><institution>Nankai University,</institution></institution-wrap>Tianjin, 300071 China</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0605 6814</institution-id><institution-id institution-id-type="GRID">grid.417024.4</institution-id><institution>Tianjin Key Laboratory of Organ Transplantation,</institution><institution>Tianjin First Center Hospital,</institution></institution-wrap>Tianjin, 300192 China</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2185 3318</institution-id><institution-id institution-id-type="GRID">grid.241167.7</institution-id><institution>Department of Cancer Biology,</institution><institution>Wake Forest University School of Medicine,</institution></institution-wrap>Winston-Salem, NC 27157 USA</aff></contrib-group><pub-date pub-type="epub"><day>11</day><month>3</month><year>2020</year></pub-date><pub-date pub-type="pmc-release"><day>11</day><month>3</month><year>2020</year></pub-date><pub-date pub-type="collection"><year>2020</year></pub-date><volume>5</volume><elocation-id>25</elocation-id><history><date date-type="received"><day>30</day><month>10</month><year>2019</year></date><date date-type="rev-recd"><day>2</day><month>1</month><year>2020</year></date><date date-type="accepted"><day>8</day><month>1</month><year>2020</year></date></history><permissions><copyright-statement>© The Author(s) 2020</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">Tumor metastasis is the most common cause of cancer-related deaths, yet it remains poorly understood. The transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) is involved in the epithelial-to-mesenchymal transition (EMT) and plays a pivotal role in tumor metastasis. However, the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown. Herein, we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo. Mechanistically, we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6. The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1. Moreover, we found a strong positive correlation between the expression of <italic>p</italic>-RB (an indicator of CDK4/6 activity), <italic>p</italic>-USP51 and ZEB1 in metastatic human breast cancer samples. Notably, the high expression of <italic>p</italic>-RB, <italic>p</italic>-USP51, and ZEB1 was significantly correlated with a poor clinical outcome. Taken together, our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Breast cancer</kwd><kwd>Epigenetics</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100006606</institution-id><institution>Natural Science Foundation of Tianjin City (Natural Science Foundation of Tianjin)</institution></institution-wrap></funding-source><award-id>17JCZDJC36600</award-id><award-id>17JCZDJC36600</award-id><award-id>17JCZDJC36600</award-id><award-id>17JCZDJC36600</award-id><award-id>17JCZDJC36600</award-id><award-id>17JCZDJC36600</award-id><award-id>17JCZDJC36600</award-id><award-id>17JCZDJC36600</award-id><award-id>17JCZDJC36600</award-id><award-id>17JCZDJC36600</award-id><award-id>17JCZDJC36600</award-id><principal-award-recipient><name><surname>Zhang</surname><given-names>Zhen</given-names></name><name><surname>Li</surname><given-names>Jianjun</given-names></name><name><surname>Ou</surname><given-names>Yang</given-names></name><name><surname>Deng</surname><given-names>Kaiyuan</given-names></name><name><surname>Wang</surname><given-names>Qiong</given-names></name><name><surname>Wang</surname><given-names>Zhaoyang</given-names></name><name><surname>Wang</surname><given-names>Wenhao</given-names></name><name><surname>Zhang</surname><given-names>Quansheng</given-names></name><name><surname>Sun</surname><given-names>Wei</given-names></name><name><surname>Sun</surname><given-names>Peiqing</given-names></name><name><surname>Yang</surname><given-names>Shuang</given-names></name></principal-award-recipient></award-group></funding-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>81472545</award-id><award-id>81472545</award-id><award-id>81472545</award-id><principal-award-recipient><name><surname>Li</surname><given-names>Jianjun</given-names></name><name><surname>Yang</surname><given-names>Guang</given-names></name><name><surname>Wang</surname><given-names>Hang</given-names></name></principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2020</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Caroline du Nord</li></region></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Zhang, Zhen" sort="Zhang, Zhen" uniqKey="Zhang Z" first="Zhen" last="Zhang">Zhen Zhang</name></noRegion><name sortKey="Deng, Kaiyuan" sort="Deng, Kaiyuan" uniqKey="Deng K" first="Kaiyuan" last="Deng">Kaiyuan Deng</name><name sortKey="Li, Jianjun" sort="Li, Jianjun" uniqKey="Li J" first="Jianjun" last="Li">Jianjun Li</name><name sortKey="Ou, Yang" sort="Ou, Yang" uniqKey="Ou Y" first="Yang" last="Ou">Yang Ou</name><name sortKey="Sun, Wei" sort="Sun, Wei" uniqKey="Sun W" first="Wei" last="Sun">Wei Sun</name><name sortKey="Wang, Hang" sort="Wang, Hang" uniqKey="Wang H" first="Hang" last="Wang">Hang Wang</name><name sortKey="Wang, Qiong" sort="Wang, Qiong" uniqKey="Wang Q" first="Qiong" last="Wang">Qiong Wang</name><name sortKey="Wang, Wenhao" sort="Wang, Wenhao" uniqKey="Wang W" first="Wenhao" last="Wang">Wenhao Wang</name><name sortKey="Wang, Zhaoyang" sort="Wang, Zhaoyang" uniqKey="Wang Z" first="Zhaoyang" last="Wang">Zhaoyang Wang</name><name sortKey="Yang, Guang" sort="Yang, Guang" uniqKey="Yang G" first="Guang" last="Yang">Guang Yang</name><name sortKey="Yang, Shuang" sort="Yang, Shuang" uniqKey="Yang S" first="Shuang" last="Yang">Shuang Yang</name><name sortKey="Zhang, Quansheng" sort="Zhang, Quansheng" uniqKey="Zhang Q" first="Quansheng" last="Zhang">Quansheng Zhang</name></country><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Sun, Peiqing" sort="Sun, Peiqing" uniqKey="Sun P" first="Peiqing" last="Sun">Peiqing Sun</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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