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

Authors

• 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

Document Type

Article

Presentation Date

6-6-2017

Comments

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.

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.

Recommended Citation

Urbanucci, Alfonso; Barfeld, Stefan J.; Kytölä, Ville; Itkonen, Harri M.; Coleman, Ilsa M.; Vodák, Daniel; Sjöblom, Liisa; Sheng, Xia; Tolonen, Teemu; Minner, Sarah; Burdelski, Christoph; Kivinummi, Kati K.; Kohvakka, Annika; Kregel, Steven; Takhar, Mandeep; Alshalalfa, Mohammed; Davicioni, Elai; Erho, Nicholas; Lloyd, Paul; Karnes, R. Jeffrey; Ross, Ashley E.; Schaeffer, Edward M.; Vander Griend, Donald J.; Knapp, Stefan; Corey, Eva; Feng, Felix Y.; Nelson, Peter S.; Saatcioglu, Fahri; Knudsen, Karen E.; Tammela, Teuvo L.J.; Sauter, Guido; Schlomm, Thorsten; Nykter, Matti; Visakorpi, Tapio; and Mills, Ian G., "Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer." (2017). Kimmel Cancer Center Papers, Presentations, and Grand Rounds. Paper 54.
https://jdc.jefferson.edu/kimmelgrandrounds/54

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.