Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):6810-6815. doi: 10.1073/pnas.1718811115. Epub 2018 May 29.

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

Author information

1
Department of Pathology, Duke University School of Medicine, Durham, NC 27710.
2
Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710.
3
Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, OH 43210.
4
Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210.
5
Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
6
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105.
7
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX 78229.
8
Department of Radiology, The Ohio State University College of Medicine, Columbus, OH 43210.
9
State Key Laboratory of Molecular Oncology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China.
10
Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287; jluo1@jhmi.edu jiaoti.huang@duke.edu qianben.wang@duke.edu.
11
Department of Pathology, Duke University School of Medicine, Durham, NC 27710; jluo1@jhmi.edu jiaoti.huang@duke.edu qianben.wang@duke.edu.

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; HoxB13; castration-resistant prostate cancer; motif-resolution cistromes

PMID:
29844167
PMCID:
PMC6042123
DOI:
10.1073/pnas.1718811115
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center