Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer.
Urbanucci A., Barfeld SJ., Kytölä V., Itkonen HM., Coleman IM., 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 TLJ., Sauter G., Schlomm T., Nykter M., Visakorpi T., Mills IG.
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.