Alfonso Urbanucci, University of Oslo; Oslo University Hospital
Stefan J. Barfeld, University of Oslo
Ville Kytölä, University of Tampere and Tampere University of Technology
Harri M. Itkonen, University of Oslo
Ilsa M. Coleman, Fred Hutchinson Cancer Research Center
Daniel Vodák, Oslo University Hospital
Liisa Sjöblom, Tampere University Hospital
Xia Sheng, University of Oslo
Teemu Tolonen, Tampere University Hospital
Sarah Minner, University Medical Center Hamburg-Eppendorf
Christoph Burdelski, University Medical Center Hamburg-Eppendorf
Kati K. Kivinummi, University of Tampere and Tampere University of Technology
Annika Kohvakka, University of Tampere and Fimlab Laboratories
Steven Kregel, University of Michigan; University of Chicago
Mandeep Takhar, GenomeDx Biosciences
Mohammed Alshalalfa, GenomeDx BiosciencesFollow
Elai Davicioni, GenomeDx BiosciencesFollow
Nicholas Erho, GenomeDx BiosciencesFollow
Paul Lloyd, University of California, San Francisco
R. Jeffrey Karnes, Mayo Clinic
Ashley E. Ross, Johns Hopkins Medical InstituteFollow
Edward M. Schaeffer, Northwestern UniversityFollow
Donald J. Vander Griend, University of Chicago
Stefan Knapp, University of Oxford; Goethe-University Frankfurt
Eva Corey, University of Washington
Felix Y. Feng, University of California at San FranciscoFollow
Peter S. Nelson, Fred Hutchinson Cancer Research Center; University of Washington
Fahri Saatcioglu, University of Oslo; Oslo University Hospital
Karen E. Knudsen, Thomas Jefferson UniversityFollow
Teuvo L.J. Tammela, University of Tampere and Tampere University Hospital
Guido Sauter, University Medical Center Hamburg-Eppendorf
Thorsten Schlomm, University Medical Center Hamburg-Eppendorf
Matti Nykter, University of Tampere and Tampere University of Technology
Tapio Visakorpi, Tampere University HospitalFollow
Ian G. Mills, Queen's University; University of Oslo; Oslo University Hospital

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This article has been peer reviewed. It is the author’s final published version in Cell Reports

Volume 19, Issue 10, June 2017, Pages 2045-2059.

The published version is available at DOI: 10.1016/j.celrep.2017.05.049. Copyright © Urbanucci et al.


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.

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