title: Impact of DNA methyltransferases on the epigenetic regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in malignant melanoma.
abstract: Aberrant promoter methylation and resultant silencing of TRAIL decoy receptors were reported in a variety of cancers, but to date little is known about the relevance of this epigenetic modification in melanoma. In this study, we examined the methylation and the expression status of TRAIL receptor genes in cutaneous and uveal melanoma cell lines and specimens and their interaction with DNA methyltransferases (DNMTs) DNMT1, DNMT3a, and DNMT3b. DR4 and DR5 methylation was not frequent in cutaneous melanoma but on the contrary it was very frequent in uveal melanoma. No correlation between methylation status of DR4 and DR5 and gene expression was found. DcR1 and DcR2 were hypermethylated with very high frequency in both cutaneous and uveal melanoma. The concordance between methylation and loss of gene expression ranged from 91% to 97%. Here we showed that DNMT1 was crucial for DcR2 hypermethylation and that DNMT1 and DNMT3a coregulate the methylation status of DcR1. Our work also revealed the critical relevance of DcR1 and DcR2 expression in cell growth and apoptosis either in cutaneous or uveal melanoma. In conclusion, the results presented here claim for a relevant impact of aberrant methylation of decoy receptors in melanoma and allow to understand how the silencing of DcR1 and DcR2 is related to melanomagenesis.
authors.affiliation: Department of Experimental Specialized Medical and Surgical and Odontostomatology Sciences, University of Messina, Messina, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Venza
authors.forename: Maria
authors.initials: M
authors.lastname: Visalli
authors.forename: Teresa
authors.initials: T
authors.lastname: Catalano
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fortunato
authors.forename: Rosaria
authors.initials: R
authors.lastname: Oteri
authors.forename: Diana
authors.initials: D
authors.lastname: Teti
authors.forename: Isabella
authors.initials: I
authors.lastname: Venza
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015257:DNA-Cytosine Methylases / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D058851:GPI-Linked Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics*; D014604:Uveal Neoplasms / Q000201:enzymology / Q000235:genetics*; D000098943:Uveal Melanoma
chemical_list: D058851:GPI-Linked Proteins; D053320:Receptors, Tumor Necrosis Factor, Member 10c; C108661:TNFRSF10C protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D015257:DNA-Cytosine Methylases
keywords: Cutaneous melanoma; DNA methyltransferases; Gene expression; Promoter methylation; TRAIL receptors; Uveal melanoma