Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

Zhong Chen; Dayong Wu; Jennifer M. Thomas-Ahner; Changxue Lu; Pei Zhao; Qingfu Zhang; Connor Geraghty; Pearlly S. Yan; William Hankey; Benjamin Sunkel; Xiaolong Cheng; Emmanuel S. Antonarakis; Qi En Wang; Zhihua Liu; Tim H.M. Huang; Victor X. Jin; Steven K. Clinton; Jun Luo; Jiaoti Huang; Qianben Wang

doi:10.1073/pnas.1718811115

Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

Zhong Chen, Dayong Wu, Jennifer M. Thomas-Ahner, Changxue Lu, Pei Zhao, Qingfu Zhang, Connor Geraghty, Pearlly S. Yan, William Hankey, Benjamin Sunkel, Xiaolong Cheng, Emmanuel S. Antonarakis, Qi En Wang, Zhihua Liu, Tim H.M. Huang, Victor X. Jin, Steven K. Clinton, Jun Luo, Jiaoti Huang, Qianben Wang

Department of Molecular Medicine

Research output: Contribution to journal › Article › peer-review

113 Scopus citations

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.

Original language	English (US)
Pages (from-to)	6810-6815
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	26
DOIs	https://doi.org/10.1073/pnas.1718811115
State	Published - Jun 26 2018

Keywords

AR-V7
Castration-resistant prostate cancer
HoxB13
Motif-resolution cistromes

ASJC Scopus subject areas

General

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10.1073/pnas.1718811115

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Chen, Z., Wu, D., Thomas-Ahner, J. M., Lu, C., Zhao, P., Zhang, Q., Geraghty, C., Yan, P. S., Hankey, W., Sunkel, B., Cheng, X., Antonarakis, E. S., Wang, Q. E., Liu, Z., Huang, T. H. M., Jin, V. X., Clinton, S. K., Luo, J., Huang, J., & Wang, Q. (2018). Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. Proceedings of the National Academy of Sciences of the United States of America, 115(26), 6810-6815. https://doi.org/10.1073/pnas.1718811115

Chen, Z, Wu, D, Thomas-Ahner, JM, Lu, C, Zhao, P, Zhang, Q, Geraghty, C, Yan, PS, Hankey, W, Sunkel, B, Cheng, X, Antonarakis, ES, Wang, QE, Liu, Z, Huang, THM, Jin, VX, Clinton, SK, Luo, J, Huang, J & Wang, Q 2018, 'Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 26, pp. 6810-6815. https://doi.org/10.1073/pnas.1718811115

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title = "Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13",

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.",

keywords = "AR-V7, Castration-resistant prostate cancer, HoxB13, Motif-resolution cistromes",

author = "Zhong Chen and Dayong Wu and Thomas-Ahner, {Jennifer M.} and Changxue Lu and Pei Zhao and Qingfu Zhang and Connor Geraghty and Yan, {Pearlly S.} and William Hankey and Benjamin Sunkel and Xiaolong Cheng and Antonarakis, {Emmanuel S.} and Wang, {Qi En} and Zhihua Liu and Huang, {Tim H.M.} and Jin, {Victor X.} and Clinton, {Steven K.} and Jun Luo and Jiaoti Huang and Qianben Wang",

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T1 - Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

AU - Chen, Zhong

AU - Wu, Dayong

AU - Thomas-Ahner, Jennifer M.

AU - Lu, Changxue

AU - Zhao, Pei

AU - Zhang, Qingfu

AU - Geraghty, Connor

AU - Yan, Pearlly S.

AU - Hankey, William

AU - Sunkel, Benjamin

AU - Cheng, Xiaolong

AU - Antonarakis, Emmanuel S.

AU - Wang, Qi En

AU - Liu, Zhihua

AU - Huang, Tim H.M.

AU - Jin, Victor X.

AU - Clinton, Steven K.

AU - Luo, Jun

AU - Huang, Jiaoti

AU - Wang, Qianben

PY - 2018/6/26

Y1 - 2018/6/26

N2 - 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.

AB - 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.

KW - AR-V7

KW - Castration-resistant prostate cancer

KW - HoxB13

KW - Motif-resolution cistromes

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Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

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