Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer.
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Anastasia Wyce1, Yan Degenhardt2, Yuchen Bai2, BaoChau Le1, Susan Korenchuk1, Ming-Chih Crouthamel1, Charles F. McHugh1, Robert Vessella3, Caretha L. Creasy1, Peter J. Tummino1, Olena Barbash1
1 Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA
2 Molecular Medicine Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA
3 Departments of Urology and Microbiology, University of Washington School of Medicine, Seattle, WA , USA
Olena Barbash, email:
Keywords: BET, Brd4, c-Myc, prostate cancer, bromodomain
Received: November 4, 2013 Accepted: November 21, 2013 Published: November 23, 2013
BET (bromodomain and extra-terminal) proteins regulate gene expression through their ability to bind to acetylated chromatin and subsequently activate RNA PolII-driven transcriptional elongation. Small molecule BET inhibitors prevent binding of BET proteins to acetylated histones and inhibit transcriptional activation of BET target genes. BET inhibitors attenuate cell growth and survival in several hematologic cancer models, partially through the down-regulation of the critical oncogene, MYC. We hypothesized that BET inhibitors will regulate MYC expression in solid tumors that frequently over-express MYC. Here we describe the effects of the highly specific BET inhibitor, I-BET762, on MYC expression in prostate cancer models. I-BET762 potently reduced MYC expression in prostate cancer cell lines and a patient-derived tumor model with subsequent inhibition of cell growth and reduction of tumor burden in vivo. Our data suggests that I-BET762 effects are partially driven by MYC down-regulation and underlines the critical importance of additional mechanisms of I-BET762 induced phenotypes.
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