RESEARCH ARTICLE Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer Neel Shah1,2, Ping Wang3, John Wongvipat1, Wouter R Karthaus1, Wassim Abida4, Joshua Armenia1, Shira Rockowitz3, Yotam Drier5, Bradley E Bernstein5, Henry W Long6, Matthew L Freedman6, Vivek K Arora7, Deyou Zheng3, Charles L Sawyers1,8* 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States; 2The Louis V. Gerstner Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States; 3Department of Neurology, Genetics and Neuroscience, Albert Einstein College of Medicine, Bronx, United States; 4Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; 5Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, United States; 6Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States; 7Division of Medical Oncology, Washington University School of Medicine, St Louis, United States; 8Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, United States Abstract In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is *For correspondence:
[email protected] adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated Competing interest: See repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both page 15 repressive signals.