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

Publication ,  Journal Article
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 ...
Published in: Proc Natl Acad Sci U S A
June 26, 2018

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 26, 2018

Volume

115

Issue

26

Start / End Page

6810 / 6815

Location

United States

Related Subject Headings

  • Up-Regulation
  • Receptors, Androgen
  • Protein Isoforms
  • Protein Binding
  • Prostatic Neoplasms, Castration-Resistant
  • Neoplasm Proteins
  • Male
  • Humans
  • Homeodomain Proteins
  • Gene Expression Regulation, Neoplastic
 

Citation

APA
Chicago
ICMJE
MLA
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Chen, Z., Wu, D., Thomas-Ahner, J. M., Lu, C., Zhao, P., Zhang, Q., … Wang, Q. (2018). Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. Proc Natl Acad Sci U S A, 115(26), 6810–6815. https://doi.org/10.1073/pnas.1718811115
Chen, Zhong, Dayong Wu, Jennifer M. Thomas-Ahner, Changxue Lu, Pei Zhao, Qingfu Zhang, Connor Geraghty, et al. “Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13.Proc Natl Acad Sci U S A 115, no. 26 (June 26, 2018): 6810–15. https://doi.org/10.1073/pnas.1718811115.
Chen Z, Wu D, Thomas-Ahner JM, Lu C, Zhao P, Zhang Q, et al. 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):6810–5.
Chen, Zhong, et al. “Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13.Proc Natl Acad Sci U S A, vol. 115, no. 26, June 2018, pp. 6810–15. Pubmed, doi:10.1073/pnas.1718811115.
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. 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.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 26, 2018

Volume

115

Issue

26

Start / End Page

6810 / 6815

Location

United States

Related Subject Headings

  • Up-Regulation
  • Receptors, Androgen
  • Protein Isoforms
  • Protein Binding
  • Prostatic Neoplasms, Castration-Resistant
  • Neoplasm Proteins
  • Male
  • Humans
  • Homeodomain Proteins
  • Gene Expression Regulation, Neoplastic