| Literature DB >> 28591577 |
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.
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.Entities:
Keywords: ATAD2; BRD2; BRD4; BROMO-10; androgen receptor; bromodomain inhibitor; castration-resistant prostate cancer; chromatin
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Year: 2017 PMID： 28591577 PMCID： PMC5675034 DOI： 10.1016/j.celrep.2017.05.049
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423