The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity
Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool o...
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| Veröffentlicht in: | Cancer cell 2013-03, Vol.23 (3), p.332-346 |
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| creator | Qi, Jianfei Tripathi, Manisha Mishra, Rajeev Sahgal, Natasha Fazil, Ladan Ettinger, Susan Placzek, William J. Claps, Giuseppina Chung, Leland W.K. Bowtell, David Gleave, Martin Bhowmick, Neil Ronai, Ze’ev A. |
| description | Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.
► A subset of chromatin-bound AR is regulated by Siah2, in concert with NCOR1 ► Siah2 regulates select AR target genes implicated in PCa proliferation and motility ► Growth of castration-resistant PCa models is inhibited upon Siah2 knockdown ► Siah2 expression is reduced during ADT and increased in CRPC |
| doi_str_mv | 10.1016/j.ccr.2013.02.016 |
| format | Article |
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► A subset of chromatin-bound AR is regulated by Siah2, in concert with NCOR1 ► Siah2 regulates select AR target genes implicated in PCa proliferation and motility ► Growth of castration-resistant PCa models is inhibited upon Siah2 knockdown ► Siah2 expression is reduced during ADT and increased in CRPC</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccr.2013.02.016</identifier><identifier>PMID: 23518348</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Castration ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Humans ; Lipid Metabolism ; Male ; Mice ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Nuclear Receptor Co-Repressor 1 - metabolism ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - metabolism ; Receptors, Androgen - metabolism ; RNA Interference ; RNA, Small Interfering ; Signal Transduction ; Transcription, Genetic ; Ubiquitin - metabolism ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism</subject><ispartof>Cancer cell, 2013-03, Vol.23 (3), p.332-346</ispartof><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><rights>2013 Elsevier Inc. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c517t-1b0f6de40b27fac62a950bf7e5209fbb5f42fe7a9768a903d8e4b993a9fe9b5a3</citedby><cites>FETCH-LOGICAL-c517t-1b0f6de40b27fac62a950bf7e5209fbb5f42fe7a9768a903d8e4b993a9fe9b5a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ccr.2013.02.016$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3536,27903,27904,45974</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23518348$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Qi, Jianfei</creatorcontrib><creatorcontrib>Tripathi, Manisha</creatorcontrib><creatorcontrib>Mishra, Rajeev</creatorcontrib><creatorcontrib>Sahgal, Natasha</creatorcontrib><creatorcontrib>Fazil, Ladan</creatorcontrib><creatorcontrib>Ettinger, Susan</creatorcontrib><creatorcontrib>Placzek, William J.</creatorcontrib><creatorcontrib>Claps, Giuseppina</creatorcontrib><creatorcontrib>Chung, Leland W.K.</creatorcontrib><creatorcontrib>Bowtell, David</creatorcontrib><creatorcontrib>Gleave, Martin</creatorcontrib><creatorcontrib>Bhowmick, Neil</creatorcontrib><creatorcontrib>Ronai, Ze’ev A.</creatorcontrib><title>The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.
► A subset of chromatin-bound AR is regulated by Siah2, in concert with NCOR1 ► Siah2 regulates select AR target genes implicated in PCa proliferation and motility ► Growth of castration-resistant PCa models is inhibited upon Siah2 knockdown ► Siah2 expression is reduced during ADT and increased in CRPC</description><subject>Animals</subject><subject>Castration</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement</subject><subject>Cell Proliferation</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Lipid Metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Nuclear Receptor Co-Repressor 1 - metabolism</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Receptors, Androgen - metabolism</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering</subject><subject>Signal Transduction</subject><subject>Transcription, Genetic</subject><subject>Ubiquitin - metabolism</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU2OEzEQhVsIxAwDB2CDvGTTjX_i7raQkKJo-JEigYbM2rLd5cRRx87Y7ki5xJyBs3AyHDKMYMPKpaqvnu33quo1wQ3BpH23bYyJDcWENZg2pfOkuiR919es7dunpeaM1y3B_UX1IqUtLgTpxPPqgjJOejbrL6v71QbQNfv541a7u8ll59HSrVUC9N2pDUWL4HN0esqQUA5ooVKOKrvg6xtILmXlM_oWQykylKk3EJE-ohtYT-NvDgWL5n6IYQ2-tA3sc4hoFZVPJrr9CVEjmpvsDi4fX1bPrBoTvHo4r6rbj9erxed6-fXTl8V8WRtOulwTjW07wAxr2lllWqoEx9p2wCkWVmtuZ9RCp0TX9kpgNvQw00IwJSwIzRW7qj6cdfeT3sFgoPxSjXIf3U7FowzKyX8n3m3kOhwk6zgWvSgCbx8EYribIGW5c8nAOCoPYUqSMCKKxZTSgpIzaopPKYJ9vIZgecpRbmXJUZ5ylJjK0ik7b_5-3-PGn-AK8P4MQHHp4CDKZBwU-wcXwWQ5BPcf-V81BLM8</recordid><startdate>20130318</startdate><enddate>20130318</enddate><creator>Qi, Jianfei</creator><creator>Tripathi, Manisha</creator><creator>Mishra, Rajeev</creator><creator>Sahgal, Natasha</creator><creator>Fazil, Ladan</creator><creator>Ettinger, Susan</creator><creator>Placzek, William J.</creator><creator>Claps, Giuseppina</creator><creator>Chung, Leland W.K.</creator><creator>Bowtell, David</creator><creator>Gleave, Martin</creator><creator>Bhowmick, Neil</creator><creator>Ronai, Ze’ev A.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130318</creationdate><title>The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity</title><author>Qi, Jianfei ; Tripathi, Manisha ; Mishra, Rajeev ; Sahgal, Natasha ; Fazil, Ladan ; Ettinger, Susan ; Placzek, William J. ; Claps, Giuseppina ; Chung, Leland W.K. ; Bowtell, David ; Gleave, Martin ; Bhowmick, Neil ; Ronai, Ze’ev A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c517t-1b0f6de40b27fac62a950bf7e5209fbb5f42fe7a9768a903d8e4b993a9fe9b5a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Castration</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement</topic><topic>Cell Proliferation</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Lipid Metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Nuclear Receptor Co-Repressor 1 - metabolism</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Receptors, Androgen - metabolism</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering</topic><topic>Signal Transduction</topic><topic>Transcription, Genetic</topic><topic>Ubiquitin - metabolism</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Qi, Jianfei</creatorcontrib><creatorcontrib>Tripathi, Manisha</creatorcontrib><creatorcontrib>Mishra, Rajeev</creatorcontrib><creatorcontrib>Sahgal, Natasha</creatorcontrib><creatorcontrib>Fazil, Ladan</creatorcontrib><creatorcontrib>Ettinger, Susan</creatorcontrib><creatorcontrib>Placzek, William J.</creatorcontrib><creatorcontrib>Claps, Giuseppina</creatorcontrib><creatorcontrib>Chung, Leland W.K.</creatorcontrib><creatorcontrib>Bowtell, David</creatorcontrib><creatorcontrib>Gleave, Martin</creatorcontrib><creatorcontrib>Bhowmick, Neil</creatorcontrib><creatorcontrib>Ronai, Ze’ev A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Qi, Jianfei</au><au>Tripathi, Manisha</au><au>Mishra, Rajeev</au><au>Sahgal, Natasha</au><au>Fazil, Ladan</au><au>Ettinger, Susan</au><au>Placzek, William J.</au><au>Claps, Giuseppina</au><au>Chung, Leland W.K.</au><au>Bowtell, David</au><au>Gleave, Martin</au><au>Bhowmick, Neil</au><au>Ronai, Ze’ev A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2013-03-18</date><risdate>2013</risdate><volume>23</volume><issue>3</issue><spage>332</spage><epage>346</epage><pages>332-346</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.
► A subset of chromatin-bound AR is regulated by Siah2, in concert with NCOR1 ► Siah2 regulates select AR target genes implicated in PCa proliferation and motility ► Growth of castration-resistant PCa models is inhibited upon Siah2 knockdown ► Siah2 expression is reduced during ADT and increased in CRPC</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23518348</pmid><doi>10.1016/j.ccr.2013.02.016</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Castration Cell Line, Tumor Cell Movement Cell Proliferation Gene Expression Regulation, Neoplastic Humans Lipid Metabolism Male Mice Nuclear Proteins - genetics Nuclear Proteins - metabolism Nuclear Receptor Co-Repressor 1 - metabolism Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Receptors, Androgen - metabolism RNA Interference RNA, Small Interfering Signal Transduction Transcription, Genetic Ubiquitin - metabolism Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism |
| title | The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity |
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