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

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

Author information

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: alfonsourbanucci@gmail.com.
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: i.g.mills@ncmm.uio.no.

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

PMID:
28591577
PMCID:
PMC5675034
DOI:
10.1016/j.celrep.2017.05.049
[Indexed for MEDLINE]
Free PMC Article

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