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- Title
A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.
- Authors
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 Fouchardière, Arnaud; Molinié, Vincent; Vabres, Pierre; Dalle, Stéphane; Poulalhon, Nicolas; Martin-Denavit, Tanguy; Thomas, Luc; Andry-Benzaquen, Pascale; Dupin, Nicolas
- Abstract
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; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. 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 (?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.
- Subjects
NEUROENDOCRINE tumors; METABOLIC disorders; NUTRITION disorders; GENETIC regulation; TRANSCRIPTION factors; BODY weight
- Publication
Nature, 2011, Vol 480, Issue 7375, p94
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature10539