A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer
- Roswell Park Cancer Institute, United States
- Cleveland Clinic, United States
- Shenzhen University, China
- QIAGEN Bioinformatics, United States
Abstract
Standard treatment for metastatic prostate cancer (CaP) prevents ligand-activation of androgen receptor (AR). Despite initial remission, CaP progresses while relying on AR. AR transcriptional output controls CaP behavior and is an alternative therapeutic target, but its molecular regulation is poorly understood. Here, we show that action of activated AR partitions into fractions that are controlled preferentially by different coregulators. In a 452-AR-target gene panel, each of 18 clinically relevant coregulators mediates androgen-responsiveness of 0%-57% genes and acts as a coactivator or corepressor in a gene-specific manner. Selectivity in coregulator-dependent AR action is reflected in differential AR binding site composition and involvement with CaP biology and progression. Isolation of a novel transcriptional mechanism in which WDR77 unites the actions of AR and p53, the major genomic drivers of lethal CaP, to control cell cycle progression provides proof-of-principle for treatment via selective interference with AR action by exploiting AR dependence on coregulators.
Data availability
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Development of coregulator-dependent androgen receptor target gene signaturesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE66722).
Article and author information
Author details
Funding
Prostate Cancer Foundation
- Hannelore Heemers
National Cancer Institute (CA166440)
- Hannelore Heemers
Velosano3
- Hannelore Heemers
National Cancer Institute (1S10RR031537-01)
- Belinda Willard
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer
eLife 6:e28482.
https://doi.org/10.7554/eLife.28482
