ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the androgen receptor
- Genentech, United States
- Novartis Institutes for BioMedical Research, United States
- Harvard Medical School, United States
- Novartis Institutes for Biomedical Research, United States
- Organovo, United States
- NIBR, United States
- Laboratoires Servier, France
- Celgene Avilomics Research, United States
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.
Article and author information
Author details
Reviewing Editor
- Scott A Armstrong, Memorial Sloan Kettering Cancer Center, United States
Version history
- Received: December 21, 2015
- Accepted: May 6, 2016
- Accepted Manuscript published: May 16, 2016 (version 1)
- Accepted Manuscript updated: May 18, 2016 (version 2)
- Version of Record published: June 15, 2016 (version 3)
Copyright
© 2016, Mounir et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the androgen receptor
eLife 5:e13964.
https://doi.org/10.7554/eLife.13964
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