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, Hui-ming Huang, Victor X Jin, Steven K. Clinton, Jun Luo, Jiaoti Huang, Qianben Wang

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)6810-6815
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number26
DOIs
StatePublished - Jun 26 2018

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Castration
Androgen Receptors
Prostatic Neoplasms
Circulating Neoplastic Cells
Oncogenes
Transcriptome
Androgens
Chromatin
Prostate
Neoplasms
Up-Regulation
Biomarkers

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. / 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, Hui-ming; Jin, Victor X; Clinton, Steven K.; Luo, Jun; Huang, Jiaoti; Wang, Qianben.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 26, 26.06.2018, p. 6810-6815.

Research output: Contribution to journalArticle

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, H, 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
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, Hui-ming ; Jin, Victor X ; Clinton, Steven K. ; Luo, Jun ; Huang, Jiaoti ; Wang, Qianben. / Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 26. pp. 6810-6815.
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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.",
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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, Hui-ming

AU - Jin, Victor X

AU - Clinton, Steven K.

AU - Luo, Jun

AU - Huang, Jiaoti

AU - Wang, Qianben

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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.

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