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Relation among oxidative stress, epigenetic alterations and malignant transformation


As other tumor types, both genetic and epigenetic alterations seem to contribute to melanoma genesis. Consistent evidences have suggested the key role of epigenetic marks in the genesis of pathologies induced by chronic stress. Increased levels of reactive oxygen species (ROS), caused for example by chronic inflammation, aging or UV radiation, might be responsible for abnormal epigenetic marks, which might significantly contribute to melanoma development. In this way, the study of the relationship among sustained stress, aberrant epigenetic marks and melanocyte malignant transformation may help to comprehend the mechanisms involved in melanoma genesis and, also, open new avenues to the development of new therapeutic strategies. Our laboratory established a murine model of melanocyte malignant transformation associated with sustained stress conditions. Progressive morphological and molecular alterations, which lead to the acquisition of malignant phenotype, were observed after submitting non-tumorigenic mefanocytes to sequential cycles of anchorage blockade. In this way, pre-malignant melanocytes corresponding to intermediate phases of malignant transformation (1C, 2C, 3C and 4C), and different melanoma cell lines, both non-metastatic (4C3- and 4C11-) and metastatic (4C3+, 4C11+, Tm1 e Tm5), were obtained from the non-tumorigenic melanocyte lineage melan-a. Data from our group demonstrated that melan-a anchorage blockade results in oxidative stress and that increased levels of superoxide anion are related to global DNA hypermethylation and increased levels of Dnmtl protein observed in this condition. We have been studied molecular mechanisms underlying alterations of epigenetic marks by ROS and the impact of this modulation on melanocyte malignant transformation. In this way, we have interested both in defining the role of the stress-responsive protein sirtuin-1 in the establishment of aberrant epigenetic marks associated with sustained stressful condition (anchorage blockade) and also in elucidating how dnmt1 transcription is affected by increased levels of ROS during melanocyte anchorage impediment. These studies may provide a better comprehension of how aberrant epigenetic marks are established in response to chronic stress conditions associated with pathological states and then contribute to the development of new therapeutic approaches. (AU)

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