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Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Jun 26; Vol. 115 (26), pp. 6810-6815. Date of Electronic Publication: 2018 May 29. - Publication Year :
- 2018
-
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.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Cell Line, Tumor
Homeodomain Proteins genetics
Humans
Male
Neoplasm Proteins genetics
Prostatic Neoplasms, Castration-Resistant genetics
Protein Binding
Protein Isoforms biosynthesis
Protein Isoforms genetics
Receptors, Androgen genetics
Alternative Splicing
Gene Expression Regulation, Neoplastic
Homeodomain Proteins metabolism
Neoplasm Proteins metabolism
Prostatic Neoplasms, Castration-Resistant metabolism
Receptors, Androgen biosynthesis
Up-Regulation
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 115
- Issue :
- 26
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 29844167
- Full Text :
- https://doi.org/10.1073/pnas.1718811115