Faculty Collaboration Database

Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. Proc Natl Acad Sci U S A 2018 Jun 26;115(26):6810-6815

Date

05/31/2018

Pubmed ID

29844167

Pubmed Central ID

PMC6042123

DOI

10.1073/pnas.1718811115

Scopus ID

2-s2.0-85049003766 (requires institutional sign-in at Scopus site)   105 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.

Author List

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 TH, Jin VX, Clinton SK, Luo J, Huang J, Wang Q

Author

Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alternative Splicing
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Homeodomain Proteins
Humans
Male
Neoplasm Proteins
Prostatic Neoplasms, Castration-Resistant
Protein Binding
Protein Isoforms
Receptors, Androgen
Up-Regulation