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Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP

Oncogene volume 35, pages 6235–6245 (2016)Cite this article

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Abstract

Restoration of tumor suppression is an attractive onco-therapeutic approach. It is particularly relevant when a tumor suppressor is excessively degraded by an overactive oncogenic E3 ligase. We previously discovered that the E6-associated protein (E6AP; as classified in the human papilloma virus context) is an E3 ligase that has an important role in the cellular stress response, and it directly targets the tumor-suppressor promyelocytic leukemia protein (PML) for proteasomal degradation. In this study, we have examined the role of the E6AP–PML axis in prostate cancer (PC). We show that knockdown (KD) of E6AP expression attenuates growth of PC cell lines in vitro. We validated this finding in vivo using cell line xenografts, patient-derived xenografts and mouse genetics. We found that KD of E6AP attenuates cancer cell growth by promoting cellular senescence in vivo, which correlates with restoration of tumor suppression by PML. In addition, we show that KD of E6AP sensitizes cells to radiation-induced death. Overall, our findings demonstrate a role for E6AP in the promotion of PC and support E6AP targeting as a novel approach for PC treatment, either alone or in combination with radiation.

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Acknowledgements

This work was supported by NHMRC project grants (1049179 and 1063389) and NHMRC Fellowship to YH (9628426), NHMRC project grant to MJH (1049720), PCF creativity grant to SW and YH, CCV grant (1085154), VCA Richard Pratt Fellowship in Prostate Cancer Research to CG, the PCFA grant (NDDA-1811) to EW, Pfizer Australia, NHMRC and Veski foundings to MS, and a prostate initiative grant from the Foundation of the Peter MacCallum Cancer Centre. PrEC line was a generous gift from Dr Patrick Humbert and Helen Pearson at Peter MacCallum Cancer Centre.

Author information

Author notes

  1. A-L Chan

    Present address: 14Current address: The Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice Branch, Gliwice, Poland.,

  2. L Lambeth

    Present address: 15Current address: Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia.,

  3. P J Paul and D Raghu: These authors contributed equally to this work.

Authors and Affiliations

  1. The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

    P J Paul, D Raghu, T Gulati & Y Haupt

  2. Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    P J Paul, D Raghu, A-L Chan, T Gulati, L Lambeth, S Haupt, C Gamell & Y Haupt

  3. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    E Takano, C Fedele, M Shackleton & S Fox

  4. Molecular Genetics of Cancer, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia

    M J Herold

  5. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia

    M J Herold

  6. Department of Physical Sciences, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    J Hagekyriakou

  7. Department of Urology, University of Washington, Seattle, WA, USA

    R L Vessella

  8. Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    C Fedele & M Shackleton

  9. Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    C Fedele, M Shackleton, S Williams & Y Haupt

  10. Australian Prostate Cancer Research Centre—Queensland University of Technology, Brisbane, Queensland, Australia

    E D Williams

  11. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia

    Y Haupt

  12. Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia

    Y Haupt

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  1. P J Paul
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Correspondence to C Gamell.

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Paul, P., Raghu, D., Chan, AL. et al. Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP. Oncogene 35, 6235–6245 (2016). https://doi.org/10.1038/onc.2016.159

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