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.
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; and Mills, Ian G., "Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer." (2017). Kimmel Cancer Center Papers, Presentations, and Grand Rounds. Paper 54.
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