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

Research output: Contribution to journalArticlepeer-review

105 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 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
Externally publishedYes

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. This work was supported by NIH Grants U54 CA217297 (to Q.W., V.X.J., and T.H.-M.H.), R01 GM120221 (to Q.W.), R01 CA200853 (to Q.W., J.H., and S.K.C.), R01 CA172603, R01 CA205001, and R01 CA212403 (to J.H.); Department of Defense Grant W81XWH-16-1-0291 (to Q.W., S.K.C., and J.H.); and the Prostate Cancer Foundation Joyce and Larry Stupski Prostate Cancer Precision Oncology Special Challenge Award (to J.H.).

Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.

Keywords

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

Fingerprint

Dive into the research topics of 'Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13'. Together they form a unique fingerprint.

Cite this