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

doi:10.1016/j.celrep.2017.05.049

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

Cell Rep. 2017 Jun 6;19(10):2045-2059. doi: 10.1016/j.celrep.2017.05.049.

Authors

Alfonso Urbanucci¹, Stefan J Barfeld², Ville Kytölä³, Harri M Itkonen², Ilsa M Coleman⁴, Daniel Vodák⁵, Liisa Sjöblom⁶, Xia Sheng⁷, Teemu Tolonen⁸, Sarah Minner⁹, Christoph Burdelski¹⁰, Kati K Kivinummi³, Annika Kohvakka⁶, Steven Kregel¹¹, Mandeep Takhar¹², Mohammed Alshalalfa¹², Elai Davicioni¹², Nicholas Erho¹², Paul Lloyd¹³, R Jeffrey Karnes¹⁴, Ashley E Ross¹⁵, Edward M Schaeffer¹⁶, Donald J Vander Griend¹⁷, Stefan Knapp¹⁸, Eva Corey¹⁹, Felix Y Feng²⁰, Peter S Nelson²¹, Fahri Saatcioglu²², Karen E Knudsen²³, Teuvo L J Tammela²⁴, Guido Sauter⁹, Thorsten Schlomm²⁵, Matti Nykter³, Tapio Visakorpi⁶, Ian G Mills²⁶

Affiliations

¹ Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, 21 0349 Oslo, Norway; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway. Electronic address: [email protected].
² Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, 21 0349 Oslo, Norway.
³ Prostate Cancer Research Center, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University of Technology, 33520 Tampere, Finland.
⁴ Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁵ Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0424 Oslo, Norway.
⁶ Prostate Cancer Research Center, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Fimlab Laboratories, Tampere University Hospital, 33520 Tampere, Finland.
⁷ Department of Biosciences, University of Oslo, 0316 Oslo, Norway.
⁸ Department of Pathology, Fimlab Laboratories, Tampere University Hospital, 33520 Tampere, Finland.
⁹ University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
¹⁰ General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
¹¹ Department of Surgery - Section of Urology, University of Chicago, Chicago, IL 60637, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109-0940, USA.
¹² Research and Development, GenomeDx Biosciences, Vancouver, BC V6B 1B8, Canada.
¹³ Department of Medicine, University of California at San Francisco, San Francisco, CA 94143-0410, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA 94143-0981, USA.
¹⁴ Department of Urology, Mayo Clinic, Rochester, MN 55902, USA.
¹⁵ Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD 21287, USA.
¹⁶ Department of Urology, Northwestern University, Feinberg School of Medicine, 303 East Chicago Avenue, Tarry 16-703, Chicago, IL 60611-3008, USA.
¹⁷ Department of Surgery - Section of Urology, University of Chicago, Chicago, IL 60637, USA.
¹⁸ Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK; Institute for Pharmaceutical Chemistry, Goethe-University Frankfurt, Campus Riedberg, Max-von Laue Strasse 9, 60438 Frankfurt am Main, Germany.
¹⁹ Department of Urology, University of Washington, Seattle, WA 98195, USA.
²⁰ Department of Medicine, University of California at San Francisco, San Francisco, CA 94143-0410, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA 94143-0981, USA; Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94115, USA.
²¹ Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Urology, University of Washington, Seattle, WA 98195, USA; Department of Pathology, University of Washington, Seattle, WA 98195, USA.
²² Department of Biosciences, University of Oslo, 0316 Oslo, Norway; Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0424 Oslo, Norway.
²³ Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
²⁴ Prostate Cancer Research Center and Department of Urology, University of Tampere and Tampere University Hospital, 33014 Tampere, Finland.
²⁵ Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg 20095, Germany.
²⁶ Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, 21 0349 Oslo, Norway; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway; PCUK Movember Centre of Excellence, CCRCB, Queen's University, Belfast BT7 1NN, Northern Ireland, UK. Electronic address: [email protected].

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: ATAD2; BRD2; BRD4; BROMO-10; androgen receptor; bromodomain inhibitor; castration-resistant prostate cancer; chromatin.

MeSH terms

ATPases Associated with Diverse Cellular Activities / biosynthesis*
ATPases Associated with Diverse Cellular Activities / genetics
Chromatin / genetics
Chromatin / metabolism*
Chromatin / pathology
Chromatin Assembly and Disassembly*
DNA-Binding Proteins / biosynthesis*
DNA-Binding Proteins / genetics
Gene Expression Regulation, Neoplastic*
Humans
Male
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Prostatic Neoplasms, Castration-Resistant / genetics
Prostatic Neoplasms, Castration-Resistant / metabolism*
Prostatic Neoplasms, Castration-Resistant / pathology
Protein Serine-Threonine Kinases / biosynthesis*
Protein Serine-Threonine Kinases / genetics
Receptors, Androgen / genetics
Receptors, Androgen / metabolism*
Transcription Factors

Substances

BRD2 protein, human
Chromatin
DNA-Binding Proteins
Neoplasm Proteins
Receptors, Androgen
Transcription Factors
Protein Serine-Threonine Kinases
ATAD2 protein, human
ATPases Associated with Diverse Cellular Activities

Abstract

MeSH terms

Substances

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