Androgen receptor deregulation drives bromodomain-mediated chromatin alterations in prostate cancer

  • 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.
Metadaten
Author: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 KnappORCiD, 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
URN:urn:nbn:de:hebis:30:3-458899
DOI:https://doi.org/10.1016/j.celrep.2017.05.049
ISSN:2211-1247
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/28591577
Parent Title (English):Cell reports
Publisher:Elsevier
Place of publication:[New York, NY]
Document Type:Article
Language:English
Year of Completion:2017
Date of first Publication:2017/07/06
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/03/15
Tag:ATAD2; BRD2; BRD4; BROMO-10; androgen receptor; bromodomain inhibitor; castration-resistant prostate cancer; chromatin
Volume:19
Issue:10
Page Number:16
First Page:2045
Last Page:2059
Note:
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
HeBIS-PPN:431862206
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0