癌症研究
基因沉默
甲基化
DNA甲基化
黑色素瘤
顺铂
生物
基因
细胞凋亡
亚硫酸氢盐测序
异位表达
转录组
分子生物学
基因表达
遗传学
化疗
作者
William J. Faller,Máirín Rafferty,Shauna Hegarty,Gabriela Gremel,Denise Ryan,Mario F. Fraga,Manel Esteller,P. Dervan,William M. Gallagher
出处
期刊:Melanoma Research
[Ovid Technologies (Wolters Kluwer)]
日期:2010-08-20
卷期号:20 (5): 392-400
被引量:54
标识
DOI:10.1097/cmr.0b013e32833d32a6
摘要
DNA methylation plays a major role in cancer by silencing tumour suppressor genes. In melanoma, only a discrete number of methylated genes have been identified so far. After the treatment of melanoma cells with a DNA methyltransferase inhibitor and subsequent transcriptomic profiling, we had identified earlier a cohort of melanoma progression-associated genes regulated by methylation. Here, we identified which of these genes are directly methylated in melanoma cell lines and tissues. First, we examined 16 genes by bisulphite sequencing in the WM793 isogenic cell line model series. Five of these genes (CYBA, FABP5, MT1E, TSPY1 and TAC1) displayed increased methylation in several invasive cell lines compared with the parental WM793 cells, indicating their involvement in progression. Next, we analyzed several matched primary/metastatic tumours using methylation-specific PCR, which revealed that MT1E (one of the five genes assessed) was methylated in the largest proportion of tumours. Examination of a larger cohort of samples showed that 1 of 17 (6%) of the benign naevi, 16 of 43 (37%) primary tumours and 6 of 13 (46%) of the metastases displayed MT1E methylation. In addition, ectopic over-expression of MT1E mediated sensitization to cisplatin-induced apoptosis. Overall, these studies suggest that MT1E is a potential tumour suppressor gene, whose loss may promote resistance to apoptosis-inducing therapies.
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