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ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the androgen receptor

  1. Zineb Mounir
  2. Joshua M Korn
  3. Thomas Westerling
  4. Fallon Lin
  5. Christina A Kirby
  6. Markus Schirle
  7. Gregg McAllister
  8. Greg Hoffman
  9. Nadire Ramadan
  10. Anke Hartung
  11. Yan Feng
  12. David Randal Kipp
  13. Christopher Quinn
  14. Michelle Fodor
  15. Jason Baird
  16. Marie Schoumacher
  17. Ronald Meyer
  18. James Deeds
  19. Gilles Buchwalter
  20. Travis Stams
  21. Nicholas Keen
  22. William R Sellers
  23. Myles Brown
  24. Raymond A Pagliarini  Is a corresponding author
  1. Genentech, United States
  2. Novartis Institutes for BioMedical Research, United States
  3. Harvard Medical School, United States
  4. Novartis Institutes for Biomedical Research, United States
  5. Organovo, United States
  6. NIBR, United States
  7. Laboratoires Servier, France
  8. Celgene Avilomics Research, United States
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Cite this article as: eLife 2016;5:e13964 doi: 10.7554/eLife.13964

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

  1. Zineb Mounir

    Genentech, South San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Joshua M Korn

    Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Thomas Westerling

    Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Fallon Lin

    Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Christina A Kirby

    Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Markus Schirle

    Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Gregg McAllister

    Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Greg Hoffman

    Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Nadire Ramadan

    Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Anke Hartung

    Organovo, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Yan Feng

    Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. David Randal Kipp

    Oncology, NIBR, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  13. Christopher Quinn

    Oncology, NIBR, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  14. Michelle Fodor

    Oncology, NIBR, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  15. Jason Baird

    Oncology, NIBR, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  16. Marie Schoumacher

    Laboratoires Servier, Neuilly-sur-Seine, France
    Competing interests
    The authors declare that no competing interests exist.

  17. Ronald Meyer

    Department of Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  18. James Deeds

    Department of Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  19. Gilles Buchwalter

    Celgene Avilomics Research, Bedford, United States
    Competing interests
    The authors declare that no competing interests exist.

  20. Travis Stams

    Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  21. Nicholas Keen

    Department of Oncology, Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  22. William R Sellers

    Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  23. Myles Brown

    Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  24. Raymond A Pagliarini

    Celgene Avilomics Research, Bedford, United States
    For correspondence
    raymond.pagliarini@novartis.com
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Scott A Armstrong, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: December 21, 2015
  2. Accepted: May 6, 2016
  3. Accepted Manuscript published: May 16, 2016 (version 1)
  4. Accepted Manuscript updated: May 18, 2016 (version 2)
  5. 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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