Mounir, ZinebKorn, Joshua MWesterling, ThomasLin, FallonKirby, Christina ASchirle, MarkusMcAllister, GreggHoffman, GregRamadan, NadireHartung, AnkeFeng, YanKipp, David RandalQuinn, ChristopherFodor, MichelleBaird, JasonSchoumacher, MarieMeyer, RonaldDeeds, JamesBuchwalter, GillesStams, TravisKeen, NicholasSellers, William RBrown, MylesPagliarini, Raymond A2016-07-142016Mounir, Z., J. M. Korn, T. Westerling, F. Lin, C. A. Kirby, M. Schirle, G. McAllister, et al. 2016. “ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor.” eLife 5 (1): e13964. doi:10.7554/eLife.13964. http://dx.doi.org/10.7554/eLife.13964.2050-084Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:27662111The 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. DOI: http://dx.doi.org/10.7554/eLife.13964.001en-USShort ReportTMPRSS2:ERGPRMT5androgen receptorprostate cancerHumanJournal Article2016-07-1410.7554/eLife.13964