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MDM4 is a key therapeutic target in cutaneous melanoma

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'.

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Authors

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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The authors declare no competing financial interests.

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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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