NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy
Identifieur interne : 000609 ( Main/Exploration ); précédent : 000608; suivant : 000610NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy
Auteurs : Toshiki Etani ; Taku Naiki ; Aya Naiki-Ito ; Takayoshi Suzuki [Japon] ; Keitaro Iida ; Satoshi Nozaki ; Hiroyuki Kato ; Yuko Nagayasu ; Shugo Suzuki ; Noriyasu Kawai ; Takahiro Yasui ; Satoru TakahashiSource :
- Journal of Clinical Medicine [ 2077-0383 ] ; 2019.
Abstract
Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC cell lines 22Rv1, PC3, and PCai1CS were treated with NCL1, and LSD1 expression and cell viability were assessed. The epigenetic effects and mechanisms of NCL1 were also evaluated. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. Chromatin immunoprecipitation analysis indicated that NCL1 induced histone H3 lysine 9 dimethylation accumulation at promoters of P21. As shown by Western blot and flow cytometry analyses, NCL1 also dose-dependently induced caspase-dependent apoptosis. The stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. Furthermore, WST-8 assay revealed that the anti-tumor effect of NCL1 was reinforced when autophagy was inhibited by chloroquine in 22Rv1 cells. Combination index analysis revealed that a concurrent use of these drugs had a synergistic effect. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC, including neuroendocrine differentiation cases, were very high, and identical to levels observed in previously examined prostate biopsy specimens. NCL1 effectively suppressed prostate cancer growth in vitro and ex vivo without adverse events via the regulation of apoptosis and autophagy, suggesting that NCL1 is a potential therapeutic agent for CRPC.
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DOI: 10.3390/jcm8040442
PubMed: 30935141
PubMed Central: 6517972
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy</title><author><name sortKey="Etani, Toshiki" sort="Etani, Toshiki" uniqKey="Etani T" first="Toshiki" last="Etani">Toshiki Etani</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Naiki, Taku" sort="Naiki, Taku" uniqKey="Naiki T" first="Taku" last="Naiki">Taku Naiki</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Naiki Ito, Aya" sort="Naiki Ito, Aya" uniqKey="Naiki Ito A" first="Aya" last="Naiki-Ito">Aya Naiki-Ito</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Takayoshi" sort="Suzuki, Takayoshi" uniqKey="Suzuki T" first="Takayoshi" last="Suzuki">Takayoshi Suzuki</name><affiliation><nlm:aff id="af3-jcm-08-00442">Department of Chemistry, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 606-0823, Japan;<email>suzukit@koto.kpu-m.ac.jp</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-jcm-08-00442">CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0015, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0015</wicri:regionArea><wicri:noRegion>Kawaguchi 332-0015</wicri:noRegion></affiliation></author><author><name sortKey="Iida, Keitaro" sort="Iida, Keitaro" uniqKey="Iida K" first="Keitaro" last="Iida">Keitaro Iida</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Nozaki, Satoshi" sort="Nozaki, Satoshi" uniqKey="Nozaki S" first="Satoshi" last="Nozaki">Satoshi Nozaki</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Kato, Hiroyuki" sort="Kato, Hiroyuki" uniqKey="Kato H" first="Hiroyuki" last="Kato">Hiroyuki Kato</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Nagayasu, Yuko" sort="Nagayasu, Yuko" uniqKey="Nagayasu Y" first="Yuko" last="Nagayasu">Yuko Nagayasu</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Shugo" sort="Suzuki, Shugo" uniqKey="Suzuki S" first="Shugo" last="Suzuki">Shugo Suzuki</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Kawai, Noriyasu" sort="Kawai, Noriyasu" uniqKey="Kawai N" first="Noriyasu" last="Kawai">Noriyasu Kawai</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Yasui, Takahiro" sort="Yasui, Takahiro" uniqKey="Yasui T" first="Takahiro" last="Yasui">Takahiro Yasui</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Takahashi, Satoru" sort="Takahashi, Satoru" uniqKey="Takahashi S" first="Satoru" last="Takahashi">Satoru Takahashi</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30935141</idno><idno type="pmc">6517972</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517972</idno><idno type="RBID">PMC:6517972</idno><idno type="doi">10.3390/jcm8040442</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000663</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000663</idno><idno type="wicri:Area/Pmc/Curation">000663</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000663</idno><idno type="wicri:Area/Pmc/Checkpoint">000560</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000560</idno><idno type="wicri:Area/Ncbi/Merge">000512</idno><idno type="wicri:Area/Ncbi/Curation">000512</idno><idno type="wicri:Area/Ncbi/Checkpoint">000512</idno><idno type="wicri:Area/Main/Merge">000609</idno><idno type="wicri:Area/Main/Curation">000609</idno><idno type="wicri:Area/Main/Exploration">000609</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy</title><author><name sortKey="Etani, Toshiki" sort="Etani, Toshiki" uniqKey="Etani T" first="Toshiki" last="Etani">Toshiki Etani</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Naiki, Taku" sort="Naiki, Taku" uniqKey="Naiki T" first="Taku" last="Naiki">Taku Naiki</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Naiki Ito, Aya" sort="Naiki Ito, Aya" uniqKey="Naiki Ito A" first="Aya" last="Naiki-Ito">Aya Naiki-Ito</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Takayoshi" sort="Suzuki, Takayoshi" uniqKey="Suzuki T" first="Takayoshi" last="Suzuki">Takayoshi Suzuki</name><affiliation><nlm:aff id="af3-jcm-08-00442">Department of Chemistry, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 606-0823, Japan;<email>suzukit@koto.kpu-m.ac.jp</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-jcm-08-00442">CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0015, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0015</wicri:regionArea><wicri:noRegion>Kawaguchi 332-0015</wicri:noRegion></affiliation></author><author><name sortKey="Iida, Keitaro" sort="Iida, Keitaro" uniqKey="Iida K" first="Keitaro" last="Iida">Keitaro Iida</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Nozaki, Satoshi" sort="Nozaki, Satoshi" uniqKey="Nozaki S" first="Satoshi" last="Nozaki">Satoshi Nozaki</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Kato, Hiroyuki" sort="Kato, Hiroyuki" uniqKey="Kato H" first="Hiroyuki" last="Kato">Hiroyuki Kato</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Nagayasu, Yuko" sort="Nagayasu, Yuko" uniqKey="Nagayasu Y" first="Yuko" last="Nagayasu">Yuko Nagayasu</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Suzuki, Shugo" sort="Suzuki, Shugo" uniqKey="Suzuki S" first="Shugo" last="Suzuki">Shugo Suzuki</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author><author><name sortKey="Kawai, Noriyasu" sort="Kawai, Noriyasu" uniqKey="Kawai N" first="Noriyasu" last="Kawai">Noriyasu Kawai</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Yasui, Takahiro" sort="Yasui, Takahiro" uniqKey="Yasui T" first="Takahiro" last="Yasui">Takahiro Yasui</name><affiliation><nlm:aff id="af1-jcm-08-00442">Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>uroetani@med.nagoya-cu.ac.jp</email> (T.E.);<email>ikeitarou1009@gmail.com</email> (K.I.);<email>snozaki@med.nagoya-cu.ac.jp</email> (S.N.);<email>n-kawai@med.nagoya-cu.ac.jp</email> (N.K.);<email>yasui@med.nagoya-cu.ac.jp</email> (T.Y.)</nlm:aff></affiliation></author><author><name sortKey="Takahashi, Satoru" sort="Takahashi, Satoru" uniqKey="Takahashi S" first="Satoru" last="Takahashi">Satoru Takahashi</name><affiliation><nlm:aff id="af2-jcm-08-00442">Department of Experimental Pathology and Tumor Biology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan;<email>ayaito@med.nagoya-cu.ac.jp</email> (A.N.-I.);<email>h.kato@med.nagoya-cu.ac.jp</email> (H.K.);<email>naga-p@dk.pdx.ne.jp</email> (Y.N.);<email>shugo@med.nagoya-cu.ac.jp</email> (S.S.);<email>sattak@med.nagoya-cu.ac.jp</email> (S.T.)</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Clinical Medicine</title><idno type="eISSN">2077-0383</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>Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC cell lines 22Rv1, PC3, and PCai1CS were treated with NCL1, and LSD1 expression and cell viability were assessed. The epigenetic effects and mechanisms of NCL1 were also evaluated. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. Chromatin immunoprecipitation analysis indicated that NCL1 induced histone H3 lysine 9 dimethylation accumulation at promoters of P21. As shown by Western blot and flow cytometry analyses, NCL1 also dose-dependently induced caspase-dependent apoptosis. The stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. Furthermore, WST-8 assay revealed that the anti-tumor effect of NCL1 was reinforced when autophagy was inhibited by chloroquine in 22Rv1 cells. Combination index analysis revealed that a concurrent use of these drugs had a synergistic effect. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC, including neuroendocrine differentiation cases, were very high, and identical to levels observed in previously examined prostate biopsy specimens. NCL1 effectively suppressed prostate cancer growth in vitro and ex vivo without adverse events via the regulation of apoptosis and autophagy, suggesting that NCL1 is a potential therapeutic agent for CRPC.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Frydenberg, M" uniqKey="Frydenberg M">M. Frydenberg</name></author><author><name sortKey="Stricker, P D" uniqKey="Stricker P">P.D. Stricker</name></author><author><name sortKey="Kaye, K W" uniqKey="Kaye K">K.W. Kaye</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Bono, J S" uniqKey="De Bono J">J.S. de Bono</name></author><author><name sortKey="Logothetis, C J" uniqKey="Logothetis C">C.J. Logothetis</name></author><author><name sortKey="Molina, A" uniqKey="Molina A">A. Molina</name></author><author><name sortKey="Fizazi, K" uniqKey="Fizazi K">K. Fizazi</name></author><author><name sortKey="North, S" uniqKey="North S">S. 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Pinkas-Kramarski</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Japon</li></country></list><tree><noCountry><name sortKey="Etani, Toshiki" sort="Etani, Toshiki" uniqKey="Etani T" first="Toshiki" last="Etani">Toshiki Etani</name><name sortKey="Iida, Keitaro" sort="Iida, Keitaro" uniqKey="Iida K" first="Keitaro" last="Iida">Keitaro Iida</name><name sortKey="Kato, Hiroyuki" sort="Kato, Hiroyuki" uniqKey="Kato H" first="Hiroyuki" last="Kato">Hiroyuki Kato</name><name sortKey="Kawai, Noriyasu" sort="Kawai, Noriyasu" uniqKey="Kawai N" first="Noriyasu" last="Kawai">Noriyasu Kawai</name><name sortKey="Nagayasu, Yuko" sort="Nagayasu, Yuko" uniqKey="Nagayasu Y" first="Yuko" last="Nagayasu">Yuko Nagayasu</name><name sortKey="Naiki Ito, Aya" sort="Naiki Ito, Aya" uniqKey="Naiki Ito A" first="Aya" last="Naiki-Ito">Aya Naiki-Ito</name><name sortKey="Naiki, Taku" sort="Naiki, Taku" uniqKey="Naiki T" first="Taku" last="Naiki">Taku Naiki</name><name sortKey="Nozaki, Satoshi" sort="Nozaki, Satoshi" uniqKey="Nozaki S" first="Satoshi" last="Nozaki">Satoshi Nozaki</name><name sortKey="Suzuki, Shugo" sort="Suzuki, Shugo" uniqKey="Suzuki S" first="Shugo" last="Suzuki">Shugo Suzuki</name><name sortKey="Takahashi, Satoru" sort="Takahashi, Satoru" uniqKey="Takahashi S" first="Satoru" last="Takahashi">Satoru Takahashi</name><name sortKey="Yasui, Takahiro" sort="Yasui, Takahiro" uniqKey="Yasui T" first="Takahiro" last="Yasui">Takahiro Yasui</name></noCountry><country name="Japon"><noRegion><name sortKey="Suzuki, Takayoshi" sort="Suzuki, Takayoshi" uniqKey="Suzuki T" first="Takayoshi" last="Suzuki">Takayoshi Suzuki</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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