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MDM4 is a key therapeutic target in cutaneous melanoma

Nature Medicine volume 18, pages 1239–1247 (2012)Cite this article

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Abstract

The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma—a highly chemotherapy-resistant disease—TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I–IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.

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Figure 1: MDM4 is frequently overexpressed in human melanoma.
Figure 2: Mdm4 overexpression promotes melanoma in mice.
Figure 3: MDM4 promotes cell proliferation and survival of human melanoma.
Figure 4: Inhibition of the MDM4-p53 interaction restores p53 activity in melanoma.
Figure 5: Therapeutic potential of targeting the MDM4-p53 pathway.
Figure 6: Targeting the MDM4-p53 pathway sensitizes melanoma cells to a BRAFV600E-inhibitor.

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Acknowledgements

We thank O.Van Goethem for excellent technical assistance. We thank P. Agostinis, P. Wolter and M. Skipper for helpful discussions and comments on the manuscript. We thank M. Cario-Andre and A. Taïed for materials from human nevi. A. Zwolinska is a recipient of a 'Het Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO)' scholarship. C. Fedele was supported by a Clare Oliver Memorial Fellowship from the Victorian Cancer Agency. M. Shackleton was supported by fellowships from Pfizer Australia and the Victorian Endowment for Science, Knowledge and Innovation (VESKI). Y. and S. Haupt were supported by the Australian National Health and Medical Research Council (nos. 509197, 1026990 and 628426) and VESKI. R.S. Lo was supported by Stand Up to Cancer, the Joint Center for Translational Medicine, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, and the Seaver Institute. This work was supported by the Intramural Research Program of the US National Institutes of Health and the National Cancer Institute, the Association for International Cancer Research (AICR), the Melbourne Melanoma Project, the Victorian Cancer Agency and the 'Belgian Foundation against Cancer'.

Author information

Authors and Affiliations

  1. Center for the Biology of Disease, Laboratory for Molecular Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium

    Agnieszka Gembarska, Flavie Luciani, Michael Dewaele, Aleksandra Zwolinska & Jean-Christophe Marine

  2. Center for Human Genetics, Katholieke Universiteit (KU) Leuven, Leuven, Belgium

    Agnieszka Gembarska, Flavie Luciani, Michael Dewaele, Aleksandra Zwolinska & Jean-Christophe Marine

  3. Melanoma Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia

    Clare Fedele & Mark Shackleton

  4. Department of Pathology, The University of Melbourne, Parkville, Australia

    Clare Fedele & Mark Shackleton

  5. Metabolism Branch, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA

    Elisabeth A Russell & Federico Bernal

  6. International Agency for Research on Cancer (IARC/CIRC), Lyon, France

    Stéphanie Villar

  7. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia

    Sue Haupt, Ygal Haupt & Mark Shackleton

  8. Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia

    Sue Haupt & Ygal Haupt

  9. Department of Molecular Cell Biology, University Medical Centre, Leiden, The Netherlands

    Job de Lange & Aart Jochemsen

  10. Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Cancer Institute of New Jersey, New Brunswick, New Jersey, USA

    Dana Yip & James Goydos

  11. Department for Molecular Biomedical Research, Vascular Cell Biology Unit, VIB, Ghent, Belgium.,

    Jody J Haigh

  12. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

    Jody J Haigh

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

    Ygal Haupt

  14. Curie Institute, Developmental Genetics of Melanocytes, Centre National de la Recherche Scientifique (CNRS) UMR3347, Institut National de la Santé et de la Recherche Médicale (INSERM) U1021, Orsay, France

    Lionel Larue

  15. Department of Medicine (Division of Dermatology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA

    Hubing Shi, Gatien Moriceau & Roger S Lo

  16. Department of Molecular and Medical Pharmacology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA

    Hubing Shi, Gatien Moriceau & Roger S Lo

  17. Institute Jules Bordet, Brussels, Belgium

    Ghanem Ghanem

Authors
  1. Agnieszka Gembarska
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Contributions

A.G. did experimental work, developed the hypothesis, analyzed the data and coordinated the project. F.L. did experimental work and analyzed the data. C.F. conducted immunofluorescence analyses in normal human skin and melanomas and analyzed the data. E.A.R. conducted cellular assays. M.D. conducted experimental work. S.V. determined the p53 status of melanoma cell lines and primary tumors. A.Z. did the chromatin immunoprecipitation experiments and analyzed the data. S.H. contributed to the development of MDM4 immunohistochemistry. J.d.L. generated MDM4 knockdown lentiviral vectors. D.Y. and J.G. obtained primary human melanoma samples. J.J.H. contributed to the mouse work and experimental design. H.S. and G.M. generated and characterized BRAF inhibitor–resistant cell lines. F.B. produced and supplied SAH-p53-8 and SAH-p53-8F19A. Y.H., L.L., A.J., R.S.L., G.G., M.S. and F.B. discussed the hypothesis and contributed to data interpretation and experimental design. J.-C.M. conceived the hypothesis, led the project, interpreted the data and wrote the manuscript.

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Correspondence to Jean-Christophe Marine.

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Gembarska, A., Luciani, F., Fedele, C. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 18, 1239–1247 (2012). https://doi.org/10.1038/nm.2863

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