학술논문
ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor
Document Type
article
Author
Zineb Mounir; Joshua M Korn; Thomas Westerling; Fallon Lin; Christina A Kirby; Markus Schirle; Gregg McAllister; Greg Hoffman; Nadire Ramadan; Anke Hartung; Yan Feng; David Randal Kipp; Christopher Quinn; Michelle Fodor; Jason Baird; Marie Schoumacher; Ronald Meyer; James Deeds; Gilles Buchwalter; Travis Stams; Nicholas Keen; William R Sellers; Myles Brown; Raymond A Pagliarini
Source
eLife, Vol 5 (2016)
Subject
Language
English
ISSN
2050-084X
Abstract
The TMPRSS2:ERG gene fusion is common in androgen receptor (AR) positive prostate cancers, yet its function remains poorly understood. From a screen for functionally relevant ERG interactors, we identify the arginine methyltransferase PRMT5. ERG recruits PRMT5 to AR-target genes, where PRMT5 methylates AR on arginine 761. This attenuates AR recruitment and transcription of genes expressed in differentiated prostate epithelium. The AR-inhibitory function of PRMT5 is restricted to TMPRSS2:ERG-positive prostate cancer cells. Mutation of this methylation site on AR results in a transcriptionally hyperactive AR, suggesting that the proliferative effects of ERG and PRMT5 are mediated through attenuating AR’s ability to induce genes normally involved in lineage differentiation. This provides a rationale for targeting PRMT5 in TMPRSS2:ERG positive prostate cancers. Moreover, methylation of AR at arginine 761 highlights a mechanism for how the ERG oncogene may coax AR towards inducing proliferation versus differentiation.