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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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, Q-E; Liu, Z; Huang, TH-M; Jin, VX; Clinton, SK; Luo, J; Huang, J; Wang, Q

Published Date

  • June 2018

Published In

Volume / Issue

  • 115 / 26

Start / End Page

  • 6810 - 6815

PubMed ID

  • 29844167

Pubmed Central ID

  • 29844167

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1718811115

Language

  • eng