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 language | English (US) |
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Pages (from-to) | 6810-6815 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 115 |
Issue number | 26 |
DOIs | |
State | Published - Jun 26 2018 |
Externally published | Yes |
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