TY - JOUR TI - ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor AU - Mounir, Zineb AU - Korn, Joshua M AU - Westerling, Thomas AU - Lin, Fallon AU - Kirby, Christina A AU - Schirle, Markus AU - McAllister, Gregg AU - Hoffman, Greg AU - Ramadan, Nadire AU - Hartung, Anke AU - Feng, Yan AU - Kipp, David Randal AU - Quinn, Christopher AU - Fodor, Michelle AU - Baird, Jason AU - Schoumacher, Marie AU - Meyer, Ronald AU - Deeds, James AU - Buchwalter, Gilles AU - Stams, Travis AU - Keen, Nicholas AU - Sellers, William R AU - Brown, Myles AU - Pagliarini, Raymond A A2 - Armstrong, Scott A VL - 5 PY - 2016 DA - 2016/05/16 SP - e13964 C1 - eLife 2016;5:e13964 DO - 10.7554/eLife.13964 UR - https://doi.org/10.7554/eLife.13964 AB - 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. KW - TMPRSS2:ERG KW - PRMT5 KW - androgen receptor KW - prostate cancer JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -