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

Alfonso Urbanucci | Zendy; Stefan J. Barfeld | Zendy; Ville Kytölä | Zendy; Harri M. Itkonen | Zendy; Ilsa M. Coleman | Zendy; Daniel Vodák | Zendy; Liisa Sjöblom | Zendy; Xia Sheng | Zendy; Teemu Tolonen | Zendy; Sarah Minner | Zendy; Christoph Burdelski | Zendy; Kati Kivinummi | Zendy; Annika Kohvakka | Zendy; Steven Kregel | Zendy; Mandeep Takhar | Zendy; Mohammed Alshalalfa | Zendy; Elai Davicioni | Zendy; Nicholas Erho | Zendy; Paul Lloyd | Zendy; R. Jeffrey Karnes | Zendy; Ashley E. Ross | Zendy; Edward M. Schaeffer | Zendy; Donald J. Vander Griend | Zendy; Stefan Knapp | Zendy; Eva Corey | Zendy; Felix Y. Feng | Zendy; Peter S. Nelson | Zendy; Fahri Saatcioglu | Zendy; Karen E. Knudsen | Zendy; Teuvo L.J. Tammela | Zendy; Guido Sauter | Zendy; Thorsten Schlomm | Zendy; Matti Nykter | Zendy; Tapio Visakorpi | Zendy; Ian G. Mills | Zendy

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

Author(s) -

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 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

Publication year - 2017

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2017.05.049

Subject(s) - prostate cancer , androgen receptor , chromatin , bromodomain , enzalutamide , deregulation , cancer research , prostate , receptor , androgen , cancer , microbiology and biotechnology , epigenetics , biology , chemistry , medicine , endocrinology , hormone , genetics , gene , macroeconomics , economics

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.

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