ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor
- PMID: 27183006
- PMCID: PMC4909395
- DOI: 10.7554/eLife.13964
ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor
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.
Keywords: PRMT5; TMPRSS2:ERG; androgen receptor; cancer biology; cell biology; human; prostate cancer.
Conflict of interest statement
ZM: was the recipient of presidential postdoctoral fellowship from the Novartis Institutes for Biomedical Research and is an employee of Genentech.
FL: employee of Novartis Institutes for Biomedical Research.
CAK: employee of Novartis Institutes for Biomedical Research.
MSch: employee of Novartis Institutes for Biomedical Research.
GM: employee of Novartis Institutes for Biomedical Research.
GH: employee of Novartis Institutes for Biomedical Research.
NR: employee of Novartis Institutes for Biomedical Research.
AH: is an employee of Organovo.
YF: employee of Novartis Institutes for Biomedical Research.
DRK: employee of Novartis Institutes for Biomedical Research.
CQ: employee of Novartis Institutes for Biomedical Research.
MF: employee of Novartis Institutes for Biomedical Research.
RM: employee of Novartis Institutes for Biomedical Research.
JD: employee of Novartis Institutes for Biomedical Research.
GB: is an employee of Celgene.
TS: employee of Novartis Institutes for Biomedical Research.
NK: employee of Novartis Institutes for Biomedical Research.
WRS: employee of Novartis Institutes for Biomedical Research.
MB: is a consultant to Novartis and the recipient of sponsored research support from Novartis.
RAP: employee of Novartis Institutes for Biomedical Research.
The other authors declare that no competing interests exist.
Figures
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