Molecular determinants for enzalutamide-induced transcription in prostate cancer.
Published
Journal Article
Enzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 globally directs enzalutamide-induced transcription by facilitating AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.
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Duke Authors
Cited Authors
- Yuan, F; Hankey, W; Wu, D; Wang, H; Somarelli, J; Armstrong, AJ; Huang, J; Chen, Z; Wang, Q
Published Date
- November 4, 2019
Published In
Volume / Issue
- 47 / 19
Start / End Page
- 10104 - 10114
PubMed ID
- 31501863
Pubmed Central ID
- 31501863
Electronic International Standard Serial Number (EISSN)
- 1362-4962
Digital Object Identifier (DOI)
- 10.1093/nar/gkz790
Language
- eng
Conference Location
- England