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Elife. 2017 Sep 11;6. pii: e27861. doi: 10.7554/eLife.27861.

Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
2
The Louis V. Gerstner Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
3
Department of Neurology, Genetics and Neuroscience, Albert Einstein College of Medicine, Bronx, United States.
4
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States.
5
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, United States.
6
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
7
Division of Medical Oncology, Washington University School of Medicine, St Louis, United States.
8
Howard 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 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 repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.

KEYWORDS:

cancer biology; epigenetics; human; mouse; prostate cancer; resistance to targeted therapies

PMID:
28891793
PMCID:
PMC5593504
DOI:
10.7554/eLife.27861
[Indexed for MEDLINE]
Free PMC Article

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