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Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13
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Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13
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Journal Article
Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13
2018
Overview
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.
Publisher
National Academy of Sciences
Subject
/ Binding
/ Gene Expression Regulation, Neoplastic
/ Genomes
/ Health
/ Homeodomain Proteins - genetics
/ Homeodomain Proteins - metabolism
/ Humans
/ Legumes
/ Male
/ Neoplasm Proteins - genetics
/ Neoplasm Proteins - metabolism
/ Prostatic Neoplasms, Castration-Resistant - genetics
/ Prostatic Neoplasms, Castration-Resistant - metabolism
/ Protein Isoforms - biosynthesis
/ Receptors, Androgen - biosynthesis
/ Receptors, Androgen - genetics
/ Tumors
