Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13
The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2018-06, Vol.115 (26), p.6810-6815 |
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| creator | Chen, Zhong Wu, Dayong Thomas-Ahner, Jennifer M. Lu, Changxue Zhao, Pei Zhang, Qingfu Geraghty, Connor Yan, Pearlly S. Hankey, William Sunkel, Benjamin Cheng, Xiaolong Antonarakis, Emmanuel S. Wang, Qi-En Liu, Zhihua Huang, Tim H.-M. Jin, Victor X. Clinton, Steven K. Luo, Jun Huang, Jiaoti Wang, Qianben |
| description | The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7–driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors. |
| doi_str_mv | 10.1073/pnas.1718811115 |
| format | Article |
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Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7–driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1718811115</identifier><identifier>PMID: 29844167</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Agricultural production ; Alternative Splicing ; Androgen receptors ; Binding ; Biological Sciences ; Biomarkers ; Castration ; Cell Line, Tumor ; Chromatin ; Environmental impact ; Food security ; Gene Expression Regulation, Neoplastic ; Genomes ; Health ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humans ; Legumes ; Male ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Prostate cancer ; Prostatic Neoplasms, Castration-Resistant - genetics ; Prostatic Neoplasms, Castration-Resistant - metabolism ; Protein Binding ; Protein Isoforms - biosynthesis ; Protein Isoforms - genetics ; Receptors, Androgen - biosynthesis ; Receptors, Androgen - genetics ; Regulatory sequences ; Therapeutic applications ; Transcription ; Tumor cells ; Tumors ; Up-Regulation ; Vegetables</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2018-06, Vol.115 (26), p.6810-6815</ispartof><rights>Volumes 1–89 and 106–114, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Jun 26, 2018</rights><rights>2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-81c7496ec6b3ae27f59181896dafcd88aed6504b857ebd3d138cf1ba1079283d3</citedby><cites>FETCH-LOGICAL-c509t-81c7496ec6b3ae27f59181896dafcd88aed6504b857ebd3d138cf1ba1079283d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26510819$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26510819$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29844167$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Zhong</creatorcontrib><creatorcontrib>Wu, Dayong</creatorcontrib><creatorcontrib>Thomas-Ahner, Jennifer M.</creatorcontrib><creatorcontrib>Lu, Changxue</creatorcontrib><creatorcontrib>Zhao, Pei</creatorcontrib><creatorcontrib>Zhang, Qingfu</creatorcontrib><creatorcontrib>Geraghty, Connor</creatorcontrib><creatorcontrib>Yan, Pearlly S.</creatorcontrib><creatorcontrib>Hankey, William</creatorcontrib><creatorcontrib>Sunkel, Benjamin</creatorcontrib><creatorcontrib>Cheng, Xiaolong</creatorcontrib><creatorcontrib>Antonarakis, Emmanuel S.</creatorcontrib><creatorcontrib>Wang, Qi-En</creatorcontrib><creatorcontrib>Liu, Zhihua</creatorcontrib><creatorcontrib>Huang, Tim H.-M.</creatorcontrib><creatorcontrib>Jin, Victor X.</creatorcontrib><creatorcontrib>Clinton, Steven K.</creatorcontrib><creatorcontrib>Luo, Jun</creatorcontrib><creatorcontrib>Huang, Jiaoti</creatorcontrib><creatorcontrib>Wang, Qianben</creatorcontrib><title>Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7–driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors.</description><subject>Agricultural production</subject><subject>Alternative Splicing</subject><subject>Androgen receptors</subject><subject>Binding</subject><subject>Biological Sciences</subject><subject>Biomarkers</subject><subject>Castration</subject><subject>Cell Line, Tumor</subject><subject>Chromatin</subject><subject>Environmental impact</subject><subject>Food security</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genomes</subject><subject>Health</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Legumes</subject><subject>Male</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms, Castration-Resistant - genetics</subject><subject>Prostatic Neoplasms, Castration-Resistant - metabolism</subject><subject>Protein Binding</subject><subject>Protein Isoforms - biosynthesis</subject><subject>Protein Isoforms - genetics</subject><subject>Receptors, Androgen - biosynthesis</subject><subject>Receptors, Androgen - genetics</subject><subject>Regulatory sequences</subject><subject>Therapeutic applications</subject><subject>Transcription</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>Up-Regulation</subject><subject>Vegetables</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1rFTEUxYNY7Gt17UoZcNPNtPcmmXxshH6oFQqCaLchk7mj83gveSbzpP3vTXm11WaThPPL4dwcxl4jHCNocbKJvhyjRmOwru4ZWyBYbJW08JwtALhujeRynx2UsgQA2xl4wfa5NVKi0gt2fTH9plyoOf3aXusmTGXOaU2lmWITfL34eUqxzVSq4uPcbHKqh5mqGgPlxmdqfqTqEWlo-tvmMt2coXjJ9ka_KvTqfj9k3z9--HZ-2V59-fT5_PSqDR3YuTUYtLSKguqFJ67HzqJBY9XgxzAY42lQHcjedJr6QQwoTBix93V2y40YxCF7v_PdbPs1DYFiTbxymzytfb51yU_ufyVOP12N6xRIjlxUg6N7g5x-banMbj2VQKuVj5S2xXGQmncaFFT03RN0mbY51vEcRwBjuFSyUic7KtSPKpnGhzAI7q4zd9eZe-ysvnj77wwP_N-SKvBmByzLnPKjrjoEg1b8AYUlnKE</recordid><startdate>20180626</startdate><enddate>20180626</enddate><creator>Chen, Zhong</creator><creator>Wu, Dayong</creator><creator>Thomas-Ahner, Jennifer M.</creator><creator>Lu, Changxue</creator><creator>Zhao, Pei</creator><creator>Zhang, Qingfu</creator><creator>Geraghty, Connor</creator><creator>Yan, Pearlly S.</creator><creator>Hankey, William</creator><creator>Sunkel, Benjamin</creator><creator>Cheng, Xiaolong</creator><creator>Antonarakis, Emmanuel S.</creator><creator>Wang, Qi-En</creator><creator>Liu, Zhihua</creator><creator>Huang, Tim H.-M.</creator><creator>Jin, Victor X.</creator><creator>Clinton, Steven K.</creator><creator>Luo, Jun</creator><creator>Huang, Jiaoti</creator><creator>Wang, Qianben</creator><general>National Academy of Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180626</creationdate><title>Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13</title><author>Chen, Zhong ; Wu, Dayong ; Thomas-Ahner, Jennifer M. ; Lu, Changxue ; Zhao, Pei ; Zhang, Qingfu ; Geraghty, Connor ; Yan, Pearlly S. ; Hankey, William ; Sunkel, Benjamin ; Cheng, Xiaolong ; Antonarakis, Emmanuel S. ; Wang, Qi-En ; Liu, Zhihua ; Huang, Tim H.-M. ; Jin, Victor X. ; Clinton, Steven K. ; Luo, Jun ; Huang, Jiaoti ; Wang, Qianben</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-81c7496ec6b3ae27f59181896dafcd88aed6504b857ebd3d138cf1ba1079283d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Agricultural production</topic><topic>Alternative Splicing</topic><topic>Androgen receptors</topic><topic>Binding</topic><topic>Biological Sciences</topic><topic>Biomarkers</topic><topic>Castration</topic><topic>Cell Line, Tumor</topic><topic>Chromatin</topic><topic>Environmental impact</topic><topic>Food security</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genomes</topic><topic>Health</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Legumes</topic><topic>Male</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms, Castration-Resistant - genetics</topic><topic>Prostatic Neoplasms, Castration-Resistant - metabolism</topic><topic>Protein Binding</topic><topic>Protein Isoforms - biosynthesis</topic><topic>Protein Isoforms - genetics</topic><topic>Receptors, Androgen - biosynthesis</topic><topic>Receptors, Androgen - genetics</topic><topic>Regulatory sequences</topic><topic>Therapeutic applications</topic><topic>Transcription</topic><topic>Tumor cells</topic><topic>Tumors</topic><topic>Up-Regulation</topic><topic>Vegetables</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Zhong</creatorcontrib><creatorcontrib>Wu, Dayong</creatorcontrib><creatorcontrib>Thomas-Ahner, Jennifer M.</creatorcontrib><creatorcontrib>Lu, Changxue</creatorcontrib><creatorcontrib>Zhao, Pei</creatorcontrib><creatorcontrib>Zhang, Qingfu</creatorcontrib><creatorcontrib>Geraghty, Connor</creatorcontrib><creatorcontrib>Yan, Pearlly S.</creatorcontrib><creatorcontrib>Hankey, William</creatorcontrib><creatorcontrib>Sunkel, Benjamin</creatorcontrib><creatorcontrib>Cheng, Xiaolong</creatorcontrib><creatorcontrib>Antonarakis, Emmanuel S.</creatorcontrib><creatorcontrib>Wang, Qi-En</creatorcontrib><creatorcontrib>Liu, Zhihua</creatorcontrib><creatorcontrib>Huang, Tim H.-M.</creatorcontrib><creatorcontrib>Jin, Victor X.</creatorcontrib><creatorcontrib>Clinton, Steven K.</creatorcontrib><creatorcontrib>Luo, Jun</creatorcontrib><creatorcontrib>Huang, Jiaoti</creatorcontrib><creatorcontrib>Wang, Qianben</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Zhong</au><au>Wu, Dayong</au><au>Thomas-Ahner, Jennifer M.</au><au>Lu, Changxue</au><au>Zhao, Pei</au><au>Zhang, Qingfu</au><au>Geraghty, Connor</au><au>Yan, Pearlly S.</au><au>Hankey, William</au><au>Sunkel, Benjamin</au><au>Cheng, Xiaolong</au><au>Antonarakis, Emmanuel S.</au><au>Wang, Qi-En</au><au>Liu, Zhihua</au><au>Huang, Tim H.-M.</au><au>Jin, Victor X.</au><au>Clinton, Steven K.</au><au>Luo, Jun</au><au>Huang, Jiaoti</au><au>Wang, Qianben</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2018-06-26</date><risdate>2018</risdate><volume>115</volume><issue>26</issue><spage>6810</spage><epage>6815</epage><pages>6810-6815</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7–driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7–driven prostate tumors.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>29844167</pmid><doi>10.1073/pnas.1718811115</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Agricultural production Alternative Splicing Androgen receptors Binding Biological Sciences Biomarkers Castration Cell Line, Tumor Chromatin Environmental impact Food security Gene Expression Regulation, Neoplastic Genomes Health Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Legumes Male Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Prostate cancer Prostatic Neoplasms, Castration-Resistant - genetics Prostatic Neoplasms, Castration-Resistant - metabolism Protein Binding Protein Isoforms - biosynthesis Protein Isoforms - genetics Receptors, Androgen - biosynthesis Receptors, Androgen - genetics Regulatory sequences Therapeutic applications Transcription Tumor cells Tumors Up-Regulation Vegetables |
| title | Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13 |
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