Molecular determinants for enzalutamide-induced transcription in prostate cancer.

Abstract

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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1093/nar/gkz790

Publication Info

Yuan, Fuwen, William Hankey, Dayong Wu, Hongyan Wang, Jason Somarelli, Andrew J Armstrong, Jiaoti Huang, Zhong Chen, et al. (2019). Molecular determinants for enzalutamide-induced transcription in prostate cancer. Nucleic acids research, 47(19). pp. 10104–10114. 10.1093/nar/gkz790 Retrieved from https://hdl.handle.net/10161/20052.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Somarelli

Jason Andrew Somarelli

Assistant Professor in Medicine
Armstrong

Andrew John Armstrong

Professor of Medicine

I am a clinical and translational investigator focused on precision therapies and biomarkers in advanced prostate and other GU cancers.  I oversee a large research team of clinical and lab based investigators focused on improving patient outcomes, preventing metastatic disease, and understanding the biology of aggressive prostate cancer.  Some key themes:
1. Predictors of sensitivity and clinical efficacy of therapies in advanced prostate cancer
2. Novel designs of clinical trials and pharmacodynamic/translational studies in prostate, kidney, bladder cancer
3. Pre-operative models for drug development of novel agents in human testing in prostate cancer
4. Novel therapies and drug development for prostate, renal, bladder, and testicular cancer
5. Design of rational combination therapies in men with metastatic hormone-refractory prostate cancer
6. Developing prognostic and predictive models for progression and survival in metastatic prostate cancer
7. Examining surrogate markers of mortality in metastatic prostate cancer
8. Clear cell and non-clear cell renal cell carcinoma: natural history, sensitivity to novel agents including mTOR and VEGF inhibition

Huang

Jiaoti Huang

The Johnston-West Endowed Department Chair of Pathology

I am a physician-scientist with clinical expertise in the pathologic diagnosis of genitourinary tumors including tumors of the prostate, bladder, kidney and testis. Another area of interest is gynecologic tumors. In my research laboratory we study prostate cancer, focusing on molecular mechanisms of carcinogenesis and tumor progression, as well as biomarkers, imaging and novel therapeutic strategies. In addition to patient care and research, I am also passionate about education. I have trained numerous residents, fellows, graduate students and postdocs.

Chen

Zhong Chen

Assistant Professor in Pathology
Wang

Qianben Wang

Banks Anderson, Sr. Distinguished Professor

Dr. Wang's laboratory is primarily focused on understanding the transcriptional and epigenetic mechanisms that drive the progression of hormone-dependent cancers. Additionally, they investigate the role of host proteases in coronavirus infection. Their recent studies aim to combine CRISPR/Cas13 technologies with nanotechnology to target undruggable transcription factors in cancers and host proteases for controlling infections caused by SARS-CoV-2 and related coronaviruses.


Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.