title: Metallothionein 1E is methylated in malignant melanoma and increases sensitivity to cisplatin-induced apoptosis.
abstract: 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.
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: William J
authors.initials: WJ
authors.lastname: Faller
authors.forename: Mairin
authors.initials: M
authors.lastname: Rafferty
authors.forename: Shauna
authors.initials: S
authors.lastname: Hegarty
authors.forename: Gabriela
authors.initials: G
authors.lastname: Gremel
authors.forename: Denise
authors.initials: D
authors.lastname: Ryan
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Peter A
authors.initials: PA
authors.lastname: Dervan
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D019175:DNA Methylation / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D046228:Microarray Analysis; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C541541:MT1E protein, human; D008668:Metallothionein; D002945:Cisplatin