ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor

eLife

Fallon Lin¹  William R Sellers¹  Myles Brown²  Christina A Kirby²  Raymond A Pagliarini³  Gregg McAllister³  Nicholas Keen⁴  Thomas Westerling⁴  Zineb Mounir⁵  Markus Schirle⁵  Joshua M Korn⁵  James Deeds⁵  Travis Stams⁵  Gilles Buchwalter⁵  Marie Schoumacher⁵  Ronald Meyer⁵  Michelle Fodor⁵  Jason Baird⁵  Christopher Quinn⁶  Anke Hartung⁶  Greg Hoffman⁶  Nadire Ramadan⁶  Yan Feng⁶  David Randal Kipp⁷ 

[1] Center for Functional Cancer Epigenetics, Harvard Medical School, Boston, United States;Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States;Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, United States;Department of Medical Oncology, Harvard Medical School, Boston, United States;Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States;Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States;Genomics Institute of the Novartis Research Foundation, Novartis Institutes for Bio Medical Resarch, San Diego, United States;

关键词: TMPRSS2:ERG;    PRMT5;    androgen receptor;    prostate cancer;   

DOI  :  10.7554/eLife.13964

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown