TY - JOUR
T1 - A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer
AU - Liu, Song
AU - Kumari, Sangeeta
AU - Hu, Qiang
AU - Senapati, Dhirodatta
AU - Venkadakrishnan, Varadha Balaji
AU - Wang, Dan
AU - Depriest, Adam D.
AU - Schlanger, Simon E.
AU - Ben-Salem, Salma
AU - Valenzuela, Malyn May
AU - Willard, Belinda
AU - Mudambi, Shaila
AU - Swetzig, Wendy M.
AU - Das, Gokul M.
AU - Shourideh, Mojgan
AU - Koochekpour, Shahriah
AU - Falzarano, Sara Moscovita
AU - Magi-Galluzzi, Cristina
AU - Yadav, Neelu
AU - Chen, Xiwei
AU - Lao, Changshi
AU - Wang, Jianmin
AU - Billaud, Jean Noel
AU - Heemers, Hannelore V.
N1 - Publisher Copyright:
©Liu et al.
PY - 2017/8/18
Y1 - 2017/8/18
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85030714552
U2 - 10.7554/eLife.28482
DO - 10.7554/eLife.28482
M3 - Article
C2 - 28826481
AN - SCOPUS:85030714552
SN - 2050-084X
VL - 6
JO - eLife
JF - eLife
M1 - e28482
ER -