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

Cell Rep. 2017 Jun 6;19(10):2045-2059. doi: 10.1016/j.celrep.2017.05.049.

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: ATAD2; BRD2; BRD4; BROMO-10; androgen receptor; bromodomain inhibitor; castration-resistant prostate cancer; chromatin.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / biosynthesis*
  • ATPases Associated with Diverse Cellular Activities / genetics
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromatin / pathology
  • Chromatin Assembly and Disassembly*
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Transcription Factors

Substances

  • BRD2 protein, human
  • Chromatin
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Receptors, Androgen
  • Transcription Factors
  • Protein-Serine-Threonine Kinases
  • ATAD2 protein, human
  • ATPases Associated with Diverse Cellular Activities