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

A Urbanucci, S Barfeld, V Kytölä, HM Itkonen, Ilsa M. Coleman, D Vodák, L Sjöblom, X Sheng, T Tolonen, S Minner, C Burdelski, KK Kivinummi, A Kohvakka, S Kregel, M Takhar, M Alshalalfa, E Davicioni, N Erho, P Lloyd, RJ KarnesAE Ross, EM Schaeffer, DJ Vander Griend, S Knapp, E Corey, FY Feng, PS Nelson, F Saatcioglu, KE Knudsen, T Tammela, G Sauter, T Schlomm, M Nykter, Tapio Visakorpi, IG Mills

Research output: Contribution to journalArticleScientificpeer-review

51 Citations (Scopus)
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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.

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

Keywords

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

Publication forum classification

  • Publication forum level 1

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