Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer
Urbanucci, A; Barfeld, S; Kytölä, V; Itkonen, HM; Coleman, Ilsa M.; Vodák, D; Sjöblom, L; Sheng, X; Tolonen, T; Minner, S; Burdelski, C; Kivinummi, KK; Kohvakka, A; Kregel, S; Takhar, M; Alshalalfa, M; Davicioni, E; Erho, N; Lloyd, P; Karnes, RJ; Ross, AE; Schaeffer, EM; Vander Griend, DJ; Knapp, S; Corey, E; Feng, FY; Nelson, PS; Saatcioglu, F; Knudsen, KE; Tammela, T; Sauter, G; Schlomm, T; Nykter, M; Visakorpi, Tapio; Mills, IG (2017)
2017
Cell Reports
Julkaisun pysyvä osoite on
https://urn.fi/urn:nbn:fi:uta-201706121923
https://urn.fi/urn:nbn:fi:uta-201706121923
Kuvaus
Peer reviewed
Tiivistelmä
<p>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.</p>
Kokoelmat
- TUNICRIS-julkaisut [20689]