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Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Original publication

DOI

10.1016/j.celrep.2017.05.049

Type

Journal article

Journal

Cell Rep

Publication Date

06/06/2017

Volume

19

Pages

2045 - 2059

Keywords

ATAD2, BRD2, BRD4, BROMO-10, androgen receptor, bromodomain inhibitor, castration-resistant prostate cancer, chromatin, ATPases Associated with Diverse Cellular Activities, Chromatin, Chromatin Assembly and Disassembly, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Male, Neoplasm Proteins, Prostatic Neoplasms, Castration-Resistant, Protein-Serine-Threonine Kinases, Receptors, Androgen