eLife (May 2016)
ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor
- Zineb Mounir,
- Joshua M Korn,
- Thomas Westerling,
- Fallon Lin,
- Christina A Kirby,
- Markus Schirle,
- Gregg McAllister,
- Greg Hoffman,
- Nadire Ramadan,
- Anke Hartung,
- Yan Feng,
- David Randal Kipp,
- Christopher Quinn,
- Michelle Fodor,
- Jason Baird,
- Marie Schoumacher,
- Ronald Meyer,
- James Deeds,
- Gilles Buchwalter,
- Travis Stams,
- Nicholas Keen,
- William R Sellers,
- Myles Brown,
- Raymond A Pagliarini
Affiliations
- Zineb Mounir
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- Joshua M Korn
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- Thomas Westerling
- Department of Medical Oncology, Harvard Medical School, Boston, United States; Center for Functional Cancer Epigenetics, Harvard Medical School, Boston, United States; Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
- Fallon Lin
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- Christina A Kirby
- Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, United States
- Markus Schirle
- Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
- Gregg McAllister
- Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
- Greg Hoffman
- Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
- Nadire Ramadan
- Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
- Anke Hartung
- Genomics Institute of the Novartis Research Foundation, Novartis Institutes for Bio Medical Resarch, San Diego, United States
- Yan Feng
- Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
- David Randal Kipp
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- Christopher Quinn
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- Michelle Fodor
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- Jason Baird
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- Marie Schoumacher
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- Ronald Meyer
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- James Deeds
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- Gilles Buchwalter
- Department of Medical Oncology, Harvard Medical School, Boston, United States; Center for Functional Cancer Epigenetics, Harvard Medical School, Boston, United States; Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
- Travis Stams
- Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, United States
- Nicholas Keen
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- William R Sellers
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- Myles Brown
- ORCiD
- Department of Medical Oncology, Harvard Medical School, Boston, United States; Center for Functional Cancer Epigenetics, Harvard Medical School, Boston, United States; Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
- Raymond A Pagliarini
- ORCiD
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
- DOI
- https://doi.org/10.7554/eLife.13964
- Journal volume & issue
-
Vol. 5
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
