Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer
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Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. / Urbanucci, Alfonso; Barfeld, Stefan J; Kytölä, Ville; Itkonen, Harri M; Coleman, Ilsa M; Vodák, Daniel; Sjöblom, Liisa; Sheng, Xia; Tolonen, Teemu; Minner, Sarah; Burdelski, Christoph; Kivinummi, Kati K; Kohvakka, Annika; Kregel, Steven; Takhar, Mandeep; Alshalalfa, Mohammed; Davicioni, Elai; Erho, Nicholas; Lloyd, Paul; Karnes, R Jeffrey; Ross, Ashley E; Schaeffer, Edward M; Vander Griend, Donald J; Knapp, Stefan; Corey, Eva; Feng, Felix Y; Nelson, Peter S; Saatcioglu, Fahri; Knudsen, Karen E; Tammela, Teuvo L J; Sauter, Guido; Schlomm, Thorsten; Nykter, Matti; Visakorpi, Tapio; Mills, Ian G.
in: CELL REP, Jahrgang 19, Nr. 10, 06.06.2017, S. 2045-2059.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer
AU - Urbanucci, Alfonso
AU - Barfeld, Stefan J
AU - Kytölä, Ville
AU - Itkonen, Harri M
AU - Coleman, Ilsa M
AU - Vodák, Daniel
AU - Sjöblom, Liisa
AU - Sheng, Xia
AU - Tolonen, Teemu
AU - Minner, Sarah
AU - Burdelski, Christoph
AU - Kivinummi, Kati K
AU - Kohvakka, Annika
AU - Kregel, Steven
AU - Takhar, Mandeep
AU - Alshalalfa, Mohammed
AU - Davicioni, Elai
AU - Erho, Nicholas
AU - Lloyd, Paul
AU - Karnes, R Jeffrey
AU - Ross, Ashley E
AU - Schaeffer, Edward M
AU - Vander Griend, Donald J
AU - Knapp, Stefan
AU - Corey, Eva
AU - Feng, Felix Y
AU - Nelson, Peter S
AU - Saatcioglu, Fahri
AU - Knudsen, Karen E
AU - Tammela, Teuvo L J
AU - Sauter, Guido
AU - Schlomm, Thorsten
AU - Nykter, Matti
AU - Visakorpi, Tapio
AU - Mills, Ian G
N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2017/6/6
Y1 - 2017/6/6
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1016/j.celrep.2017.05.049
DO - 10.1016/j.celrep.2017.05.049
M3 - SCORING: Journal article
C2 - 28591577
VL - 19
SP - 2045
EP - 2059
JO - CELL REP
JF - CELL REP
SN - 2211-1247
IS - 10
ER -