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Elife. 2017 Aug 18;6. pii: e28482. doi: 10.7554/eLife.28482.

A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer.

Author information

1
Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, United States.
2
Department of Cancer Biology, Cleveland Clinic, Cleveland, United States.
3
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, United States.
4
Department of Research Core Services, Cleveland Clinic, Cleveland, United States.
5
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States.
6
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, United States.
7
Department of Anatomic Pathology, Cleveland Clinic, Cleveland, United States.
8
Institute for Nanosurface Science and Engineering, Shenzhen University, Shenzhen, China.
9
QIAGEN Bioinformatics, Redwood City, United States.
10
Department of Urology, Cleveland Clinic, Cleveland, United States.
11
Department of Hematology/Medical Oncology, Cleveland Clinic, Cleveland, United States.
#
Contributed equally

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.

KEYWORDS:

androgen deprivation therapy; cancer biology; castration; castration-resistant; coactivator; corepressor; human; transcription

PMID:
28826481
PMCID:
PMC5608510
DOI:
10.7554/eLife.28482
[Indexed for MEDLINE]
Free PMC Article

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