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Elife. 2016 May 16;5. pii: e13964. doi: 10.7554/eLife.13964.

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

Author information

1
Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
2
Department of Medical Oncology, Harvard Medical School, Boston, United States.
3
Center for Functional Cancer Epigenetics, Harvard Medical School, Boston, United States.
4
Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
5
Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, United States.
6
Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States.
7
Genomics Institute of the Novartis Research Foundation, Novartis Institutes for Bio Medical Resarch, San Diego, 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.

KEYWORDS:

PRMT5; TMPRSS2:ERG; androgen receptor; cancer biology; cell biology; human; prostate cancer

PMID:
27183006
PMCID:
PMC4909395
DOI:
10.7554/eLife.13964
[Indexed for MEDLINE]
Free PMC Article

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