Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation

Ana Cristina C Campos, Fernanda Molognoni, Fabiana H Melo, Luciano C Galdieri, Célia R Carneiro, Vânia D'Almeida, Mariangela Correa and Miriam G Jasiulionis

Year 2007, Volume 9, Issue 12

Abstract

Both oxidative/nitrosative stress and alterations in DNA methylation are observed during carcinogenesis of different tumor types, but no clear correlation between these events has been demonstrated until now. Melanoma cell lines were previously established after submitting the non-tumorigenic melanocyte lineage, melan-a, to cycles of anchorage blockade. In this work, increased intracellular oxidative species and nitric oxide levels, as well as alterations in the DNA methylation, were observed after melan-a detachment, which were also associated with a decrease in intracellular homocysteine, an element in the methionine (universal methyl donor) cycle. This alteration was accompanied by an increase in GSH levels and methylated DNA content. Furthermore, a significant increase in dnmt 1 and 3b expression was identified along melan-a anchorage blockade. L-NAME, known as a NOS inhibitor, and NAC prevented the increase in global DNA methylation, as well as the increase in dnmt1 and 3b expression, observed during melan-a detachment. Interestingly, both L-NAME and NAC did not inhibit NO production in these cells, but abrogated superoxide anion production during anchorage blockade. In conclusion, oxidative stress observed during melanocyte anchorage blockade seems to modulate DNA methylation levels and may directly contribute to the acquisition of an anoikis resistant phenotype through an epigenetic mechanism.

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