Ras and Rac1, frequently mutated in melanomas, are activated by superoxide anion, modulate Dnmt1 level and are causally related to melanocyte malignant transformation

PloS One
Fernanda MolognoniMiriam G Jasiulionis

Abstract

A melanocyte malignant transformation model was developed in our laboratory, in which different melanoma cell lines were obtained after submitting the non-tumorigenic melanocyte lineage melan-a to sequential cycles of anchorage impediment. Our group has already showed that increased superoxide level leads to global DNA hypermemethylation as well increased Dnmt1 expression few hours after melanocyte anchorage blockade. Here, we showed that Ras/Rac1/ERK signaling pathway is activated in melanocytes submitted to anchorage impediment, regulating superoxide levels, global DNA methylation, and Dnmt1 expression. Interestingly, Ras and Rac1 activation is not related to codon mutations, but instead regulated by superoxide. Moreover, the malignant transformation was drastically compromised when melan-a melanocytes were submitted to sequential cycles of anchorage blockage in the presence of a superoxide scavenger. This aberrant signaling pathway associated with a sustained stressful condition, which might be similar to conditions such as UV radiation and inflammation, seems to be an early step in malignant transformation and to contribute to an epigenetic reprogramming and the melanoma development.

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Citations

Mar 26, 2014·The International Journal of Biochemistry & Cell Biology·Nivea Dias AmoedoFranklin David Rumjanek
Jun 13, 2015·Oxidative Medicine and Cellular Longevity·Mario VenzaIsabella Venza
Jun 9, 2016·Free Radical Biology & Medicine·Waylan K BesslerBrian K Stansfield
Apr 27, 2017·Reproductive Sciences·Fuminori ItoHiroshi Kobayashi
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Feb 28, 2018·Frontiers in Immunology·Miriam G Jasiulionis
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Mar 2, 2019·Cancer Metastasis Reviews·Valéry L PayenPierre Sonveaux
Jan 30, 2021·Analytical Cellular Pathology (Amsterdam)·Ai-Lan LiQing-Feng Wang
Apr 13, 2021·Neoplasia : an International Journal for Oncology Research·Diogo de Oliveira PessoaMiriam Galvonas Jasiulionis

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Methods Mentioned

BETA
flow cytometry
PCR
FACS
Assay
PMA

Software Mentioned

GraphPad Prism
ImageJ
Image
pro
Media
GraphPad Prism®

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