Cell Reports (Jun 2017)
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 Karnes,
- Ashley 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
Affiliations
- Alfonso Urbanucci
- Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, 21 0349 Oslo, Norway
- Stefan J. Barfeld
- Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, 21 0349 Oslo, Norway
- Ville Kytölä
- Prostate Cancer Research Center, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University of Technology, 33520 Tampere, Finland
- Harri M. Itkonen
- Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, 21 0349 Oslo, Norway
- Ilsa M. Coleman
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
- Daniel Vodák
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0424 Oslo, Norway
- Liisa Sjöblom
- Prostate Cancer Research Center, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Fimlab Laboratories, Tampere University Hospital, 33520 Tampere, Finland
- Xia Sheng
- Department of Biosciences, University of Oslo, 0316 Oslo, Norway
- Teemu Tolonen
- Department of Pathology, Fimlab Laboratories, Tampere University Hospital, 33520 Tampere, Finland
- Sarah Minner
- University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Christoph Burdelski
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Kati K. Kivinummi
- Prostate Cancer Research Center, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University of Technology, 33520 Tampere, Finland
- Annika Kohvakka
- Prostate Cancer Research Center, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Fimlab Laboratories, Tampere University Hospital, 33520 Tampere, Finland
- Steven Kregel
- Department of Surgery - Section of Urology, University of Chicago, Chicago, IL 60637, USA
- Mandeep Takhar
- Research and Development, GenomeDx Biosciences, Vancouver, BC V6B 1B8, Canada
- Mohammed Alshalalfa
- Research and Development, GenomeDx Biosciences, Vancouver, BC V6B 1B8, Canada
- Elai Davicioni
- Research and Development, GenomeDx Biosciences, Vancouver, BC V6B 1B8, Canada
- Nicholas Erho
- Research and Development, GenomeDx Biosciences, Vancouver, BC V6B 1B8, Canada
- Paul Lloyd
- Department of Medicine, University of California at San Francisco, San Francisco, CA 94143-0410, USA
- R. Jeffrey Karnes
- Department of Urology, Mayo Clinic, Rochester, MN 55902, USA
- Ashley E. Ross
- Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD 21287, USA
- Edward M. Schaeffer
- Department of Urology, Northwestern University, Feinberg School of Medicine, 303 East Chicago Avenue, Tarry 16-703, Chicago, IL 60611-3008, USA
- Donald J. Vander Griend
- Department of Surgery - Section of Urology, University of Chicago, Chicago, IL 60637, USA
- Stefan Knapp
- Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK
- Eva Corey
- Department of Urology, University of Washington, Seattle, WA 98195, USA
- Felix Y. Feng
- Department of Medicine, University of California at San Francisco, San Francisco, CA 94143-0410, USA
- Peter S. Nelson
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
- Fahri Saatcioglu
- Department of Biosciences, University of Oslo, 0316 Oslo, Norway
- Karen E. Knudsen
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Teuvo L.J. Tammela
- Prostate Cancer Research Center and Department of Urology, University of Tampere and Tampere University Hospital, 33014 Tampere, Finland
- Guido Sauter
- University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
- Thorsten Schlomm
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg 20095, Germany
- Matti Nykter
- Prostate Cancer Research Center, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University of Technology, 33520 Tampere, Finland
- Tapio Visakorpi
- Prostate Cancer Research Center, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Fimlab Laboratories, Tampere University Hospital, 33520 Tampere, Finland
- Ian G. Mills
- Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, 21 0349 Oslo, Norway
- DOI
- https://doi.org/10.1016/j.celrep.2017.05.049
- Journal volume & issue
-
Vol. 19,
no. 10
pp. 2045 – 2059
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
- castration-resistant prostate cancer
- BROMO-10
- chromatin
- ATAD2
- BRD2
- BRD4
- androgen receptor
- bromodomain inhibitor
