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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 26; pp. 6810 - 6815
• Main Authors: Chen, Zhong, Wu, Dayong, Thomas-Ahner, Jennifer M., Lu, Changxue, Zhao, Pei, Zhang, Qingfu, Geraghty, Connor, Yan, Pearlly S., Hankey, William, Sunkel, Benjamin, Cheng, Xiaolong, Antonarakis, Emmanuel S., Wang, Qi-En, Liu, Zhihua, Huang, Tim H.-M., Jin, Victor X., Clinton, Steven K., Luo, Jun, Huang, Jiaoti, Wang, Qianben
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.06.2018
• Series: From the Cover
• Subjects: Agricultural production; Alternative Splicing; Androgen receptors; Binding; Biological Sciences; Biomarkers; Cancer; Castration; Cell Line, Tumor; Chromatin; Environmental impact; Food security; Gene Expression Regulation, Neoplastic; Genomes; Health; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Legumes; Male; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Protein Binding; Protein Isoforms - biosynthesis; Protein Isoforms - genetics; Receptors, Androgen - biosynthesis; Receptors, Androgen - genetics; Regulatory sequences; Therapeutic applications; Tissues; Transcription; Tumor cells; Tumors; Up-Regulation; Vegetables; HoxB13; castration-resistant prostate cancer; AR-V7; motif-resolution cistromes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1718811115

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.