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

Neel Shah, Ping Wang, John Wongvipat, Wouter R. Karthaus, Wassim Abida, Joshua Armenia, Shira Rockowitz, Yotam Drier, Bradley E. Bernstein, Henry W. Long, Matthew L. Freedman, Vivek K. Arora, Deyou Zheng, Charles L. Sawyers

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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.

Original languageEnglish (US)
Article numbere27861
JournaleLife
Volume6
DOIs
StatePublished - Sep 11 2017

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Shah, N., Wang, P., Wongvipat, J., Karthaus, W. R., Abida, W., Armenia, J., Rockowitz, S., Drier, Y., Bernstein, B. E., Long, H. W., Freedman, M. L., Arora, V. K., Zheng, D., & Sawyers, C. L. (2017). Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. eLife, 6, [e27861]. https://doi.org/10.7554/eLife.27861