The proto-oncogenes ETV1, ETV4 and ETV5 encode transcription factors in the E26 transformation-specific (ETS) family, which includes the most frequently rearranged and overexpressed genes in prostate cancer1,2,3,4. Despite being critical regulators of development, little is known about their post-translational regulation. Here we identify the ubiquitin ligase COP1 (also known as RFWD2) as a tumour suppressor that negatively regulates ETV1, ETV4 and ETV5. ETV1, which is mutated in prostate cancer more often, was degraded after being ubiquitinated by COP1. Truncated ETV1 encoded by prostate cancer translocation TMPRSS2:ETV1 lacks the critical COP1 binding motifs and was 50-fold more stable than wild-type ETV1. Almost all patient translocations render ETV1 insensitive to COP1, implying that this confers a selective advantage to prostate epithelial cells. Indeed, COP1 deficiency in mouse prostate elevated ETV1 and produced increased cell proliferation, hyperplasia, and early prostate intraepithelial neoplasia. Combined loss of COP1 and PTEN enhanced the invasiveness of mouse prostate adenocarcinomas. Finally, rare human prostate cancer samples showed hemizygous loss of the COP1 gene, loss of COP1 protein, and elevated ETV1 protein while lacking a translocation event. These findings identify COP1 as a tumour suppressor whose downregulation promotes prostatic epithelial cell proliferation and tumorigenesis.

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Microarray data has been deposited with the Gene Expression Omnibus under accession codes GSE27914.


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We thank E. White and A. Chinnaiyan for reagents, B. Bolon for pathology support, and D. Dunlap for in situ hybridization.

Author information

Author notes

    • Alberto C. Vitari
    •  & Wei-Qiang Gao

    Present addresses: Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California 94608, USA (A.C.V.); Renji-MedX Clinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China (W.-Q.G.).


  1. Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Alberto C. Vitari
    • , Kim Newton
    • , Karen O’Rourke
    •  & Vishva M. Dixit
  2. Department of Research Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Kevin G. Leong
  3. Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Cindy Yee
    •  & Wei-Qiang Gao
  4. Department of Bioinformatics and Computational Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Jinfeng Liu
  5. Department of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Lilian Phu
    •  & David Arnott
  6. Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Rajesh Vij
    •  & Jo-Anne Hongo
  7. Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Ronald Ferrando
    • , Suzana S. Couto
    •  & Dorothy M. French
  8. Department of Molecular Diagnostics & Cancer Cell Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Sankar Mohan
    •  & Ajay Pandita
  9. Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Ingrid E. Wertz


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A.C.V. designed and performed in vitro experiments. A.C.V., K.G.L., C.Y. and W.-Q.G. designed and performed in vivo experiments. K.N. designed and generated the Cop1 mutant mice. R.V., R.F. and J.-A.H. generated monoclonal antibodies and performed immunohistochemistry. K.O. made constructs. J.L. performed bioinformatics analyses. S.M. and A.P. designed and performed FISH experiments. L.P. and D.A. designed and performed mass spectrometry experiments. S.S.C. and D.M.F. assessed the histopathology of mouse and human tissues. A.C.V., K.G.L., K.N., K.O., J.L., L.P., R.F., S.M., A.P., D.A., D.M.F. and V.M.D. prepared the manuscript and figures. A.C.V., K.G.L., K.N., C.Y., J.L., R.F., S.M., A.P., D.A., I.E.W., W.-Q.G., D.M.F. and V.M.D. contributed to the study design and data analyses.

Competing interests

All authors were employees of Genentech, Inc.

Corresponding author

Correspondence to Vishva M. Dixit.

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