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

Proceedings of the National Academy of Sciences of the United States of America
Zhong ChenQianben Wang

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 pivo...Continue Reading

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Citations

Oct 20, 2018·The Journal of Clinical Investigation·Adam SharpStephen R Plymate
Feb 20, 2019·Endocrine-related Cancer·Peder Rustøen Braadland, Alfonso Urbanucci
Mar 14, 2019·Endocrine-related Cancer·Suzan StellooWilbert Zwart
Jul 2, 2019·The Journal of Clinical Investigation·Adeline BergerDavid S Rickman
Mar 8, 2019·Endocrine-related Cancer·Peder Rustøen Braadland, Alfonso Urbanucci
Mar 11, 2020·Nature Reviews. Clinical Oncology·Álvaro Quintanal-VillalongaCharles M Rudin
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Jun 13, 2018·Proceedings of the National Academy of Sciences of the United States of America·Héctor I Navarro, Andrew S Goldstein
Mar 7, 2020·Prostate Cancer and Prostatic Diseases·Changxue LuJun Luo
Dec 24, 2018·Proceedings of the National Academy of Sciences of the United States of America·Giorgia ZadraMassimo Loda
Jun 16, 2019·International Journal of Molecular Sciences·Simon J BaumgartBernard Haendler
Jul 22, 2020·Nature Genetics·Mark M PomerantzMatthew L Freedman
Jun 18, 2020·Scientific Reports·Jingjing LiuAntoinette Hollestelle
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Jun 23, 2021·Journal of Experimental & Clinical Cancer Research : CR·Yuning LiaoHongbiao Huang

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