Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer Journal Article
| Authors: | 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. |
| Article Title: | Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer |
| 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. © Shah et al. |
| Keywords: | immunohistochemistry; controlled study; human cell; sequence analysis; flow cytometry; genetic analysis; reverse transcription polymerase chain reaction; gene expression; gene locus; genetic transcription; cancer resistance; prostate cancer; xenograft; chromatin immunoprecipitation; upregulation; gene silencing; testosterone; transcriptome; glucocorticoid receptor; genetic regulation; histone modification; enzalutamide; antiandrogen therapy; human; article; bromodomain inhibitor |
| Journal Title: | eLife |
| Volume: | 6 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2017-09-11 |
| Start Page: | e27861 |
| Language: | English |
| DOI: | 10.7554/eLife.27861 |
| PROVIDER: | scopus |
| PMCID: | PMC5593504 |
| PUBMED: | 28891793 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 October 2017 -- Source: Scopus |
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