A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

作者：Bertolotto Corine; Lesueur Fabienne; Giuliano Sandy; Strub Thomas; de Lichy Mahaut; Bille Karine; Dessen Philippe; d'Hayer Benoit; Mohamdi Hamida; Remenieras Audrey; Maubec Eve; de la Fouchardiere Arnaud; Molinie Vincent; Vabres Pierre; Dalle Stephane; Poulalhon Nicolas; Martin Denavit Tanguy; Thomas Luc; Andry Benzaquen Pascale; Dupin Nicolas; Boitier Francoise; Rossi Annick; Perrot Jean Luc; Labeille Bruno; Robert Caroline; Escudier Bernard; Caron Olivier

来源：Nature, 2011, 480(7375): 94-U259.

DOI：10.1038/nature10539

So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (Psi KXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.

• 出版日期2011-12-1
• 单位中国地震局