A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
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DOI：
10.1038/nature10539
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发表时间：
2011-12-01
期刊：
影响因子：
64.8
通讯作者：
Bressac-de Paillerets, Brigitte
中科院分区：
文献类型：
--
作者：
Bertolotto, Corine;Lesueur, Fabienne;Bressac-de Paillerets, Brigitte
到目前为止，没有共同的环境和/或表型因素与黑色素瘤和肾细胞癌（RCC）。黑色素瘤的已知风险因素包括阳光照射，色素沉着和痣表型（1）;与RCC相关的风险因素包括吸烟，肥胖和高血压（2）。最近对同一患者中共存的黑色素瘤和RCC的研究支持这两种癌症之间相关性的遗传易感性（3）。小眼症相关转录因子（MITF）被认为是黑色素瘤癌基因（4）;它还刺激缺氧诱导因子（5）（HIF 1A）的转录，其途径是肾癌易感基因的靶向（6）。因此，我们提出MITF可能在赋予黑色素瘤和RCC并存的遗传易感性方面发挥作用。在这里，我们确定了MITF（Mi-E318 K）中的种系错义置换，与对照组相比，MITF（Mi-E318 K）在受黑色素瘤、RCC或两种癌症影响的遗传富集患者中发生的频率显著更高。总体而言，Mi-E318 K携带者患黑色素瘤、RCC或两种癌症的风险增加了五倍以上。密码子318位于小泛素样修饰物（SUMO）共有位点（Psi KXE），Mi-E318 K严重损害MITF的SUMO化。与野生型MITF相比，Mi-E318 K增强了MITF蛋白与HIF 1A启动子的结合，并增加了其转录活性。此外，我们观察到Mi-E318 K占据位点的总体增加。在RCC细胞系中，基因表达谱鉴定了与细胞生长、增殖和炎症相关的Mi-E318 K特征。最后，突变蛋白增强了黑素细胞和肾细胞的克隆形成、迁移和侵袭，这与肿瘤发生中的功能获得作用一致。我们的数据提供了对SUMO化，转录和癌症之间联系的见解。
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.