MDM4 is a key therapeutic target in cutaneous melanoma

Agnieszka Gembarska, Flavie Luciani, Clare Fedele, Elisabeth A. Russell, Michael Dewaele, Stéphanie Villar, Aleksandra Zwolinska, Sue Haupt, Job de Lange, Dana Yip, James Goydos, Jody J. Haigh, Ygal Haupt, Lionel Larue, Aart Jochemsen, Hubing Shi, Gatien Moriceau, Roger S. Lo, Ghanem Ghanem, Mark ShackletonFederico Bernal, Jean-Christophe Marine

Research output: Contribution to journalArticleAcademicpeer-review

240 Citations (Scopus)


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. © 2012 Nature America, Inc. All rights reserved.
Original languageEnglish
Pages (from-to)1239-1247
JournalNature medicine
Issue number8
Publication statusPublished - 2012

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