GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance
Abstract
Genomic amplification of the androgen receptor (AR) is an established mechanism of antiandrogen resistance in prostate cancer. Here, we show that the magnitude of AR signaling output, independent of AR genomic alteration or expression level, also contributes to antiandrogen resistance, through upregulation of the coactivator GREB1. We demonstrate 100-fold heterogeneity in AR output within human prostate cancer cell lines and show that cells with high AR output have reduced sensitivity to enzalutamide. Through transcriptomic and shRNA knockdown studies, together with analysis of clinical datasets, we identify GREB1 as a gene responsible for high AR output. We show that GREB1 is an AR target gene that amplifies AR output by enhancing AR DNA binding and promoting EP300 recruitment. GREB1 knockdown in high AR output cells restores enzalutamide sensitivity in vivo. Thus, GREB1 is a candidate driver of enzalutamide resistance through a novel feed forward mechanism.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 15, 2019
- Source ID
- 10.7554/elife.41913
Entities
People
- Anuradha Gopalan
- Charles Sawyers
- Danielle Choi
- Deyou Zheng
- Eugine Lee
- John Wongvipat
- Philip A. Watson
- Ping Wang
- Young Sun Lee
Organizations
- Albert Einstein College of Medicine
- Howard Hughes Medical Institute
- Memorial Sloan Kettering Cancer Center
- National Institutes of Health
- The Starr Foundation
- United States Department of Defense