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

Alfonso Urbanucci, Stefan J. Barfeld, Ville Kytölä, Harri M. Itkonen, Ilsa M. Coleman, Daniel Vodák, Liisa Sjöblom, Xia Sheng, Teemu Tolonen, Sarah Minner, Christoph Burdelski, Kati K. Kivinummi, Annika Kohvakka, Steven Kregel, Mandeep Takhar, Mohammed Alshalalfa, Elai Davicioni, Nicholas Erho, Paul Lloyd, R. Jeffrey KarnesAshley E. Ross, Edward M. Schaeffer, Donald J. Vander Griend, Stefan Knapp, Eva Corey, Felix Y. Feng, Peter S. Nelson, Fahri Saatcioglu, Karen E. Knudsen, Teuvo L.J. Tammela, Guido Sauter, Thorsten Schlomm, Matti Nykter, Tapio Visakorpi, Ian G. Mills

Research output: Contribution to journalArticle

41 Scopus citations

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 (US)
Pages (from-to)2045-2059
Number of pages15
JournalCell reports
Volume19
Issue number10
DOIs
StatePublished - Jun 6 2017

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Urbanucci, A., Barfeld, S. J., Kytölä, V., Itkonen, H. M., Coleman, I. M., Vodák, D., Sjöblom, L., Sheng, X., Tolonen, T., Minner, S., Burdelski, C., Kivinummi, K. K., Kohvakka, A., Kregel, S., Takhar, M., Alshalalfa, M., Davicioni, E., Erho, N., Lloyd, P., ... Mills, I. G. (2017). Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. Cell reports, 19(10), 2045-2059. https://doi.org/10.1016/j.celrep.2017.05.049