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Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

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Details

Original languageEnglish
Pages (from-to)2045-2059
Number of pages15
JournalCell Reports
Volume19
Issue number10
DOIs
Publication statusPublished - 6 Jun 2017
Publication typeA1 Journal article-refereed

Abstract

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.

Keywords

  • androgen receptor, ATAD2, BRD2, BRD4, BROMO-10, bromodomain inhibitor, castration-resistant prostate cancer, chromatin

Publication forum classification

Field of science, Statistics Finland

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