ORIGINAL ARTICLES: Translational researchMetallothionein 1E is methylated in malignant melanoma and increases sensitivity to cisplatin-induced apoptosisFaller, William J.a; Rafferty, Mairina; Hegarty, Shaunab c; Gremel, Gabrielaa; Ryan, Denisea; Fraga, Mario F.d; Esteller, Manele; Dervan, Peter A.b; Gallagher, William M.aAuthor Information aUCD School of Biomolecular and Biomedical Science bUCD School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Ireland cSchool of Medicine, Dentistry and Biomedical Science, Institute of Pathology, Queen's University Belfast, Belfast, United Kingdom dDepartment of Immunology and Oncology, National Centre for Biotechnology, CNB-CSIC, Cantoblanco, Madrid eCancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain Correspondence to Professor William M. Gallagher, PhD, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland Tel: +353 1 7166743; fax: +353 1 7166456; e-mail: [email protected] Received 14 January 2010 Accepted 19 May 2010 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website ([email protected]). The work was performed at the UCD Conway Institute, University College Dublin, Dublin, Ireland. Melanoma Research: October 2010 - Volume 20 - Issue 5 - p 392-400 doi: 10.1097/CMR.0b013e32833d32a6 Buy SDC Metrics 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. © 2010 Lippincott Williams & Wilkins, Inc.