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.
Highlights
Evidence has linked chronic cellular stress with increased risk for many diseases, including cancer [1]
This process is a stressful situation for cells and during the first hours of cell-matrix interaction loss, increased superoxide anion and nitric oxide levels, as well alterations in Dnmt1 expression and global DNA methylation were observed [5]
It was shown that both L-NAME (NOS inhibitor) and N-acetylcysteine treatment abrogate global DNA methylation increase and Dnmt1 expression observed in melan-a melanocyte lineage submitted to this stressful condition
Summary
Evidence has linked chronic cellular stress with increased risk for many diseases, including cancer [1]. For example, that repression of tumor suppressor genes linked to DNA methylation is regulated by Ras, an important oncogene [19,20,21], known as a gene driving melanoma progression [22,23] In this way, the aim of the present work was to understand how superoxide anion could change DNA methylation levels and identify the cellular signaling pathways involved. We showed that Ras/Rac1/MEK/ERK signaling pathway is regulated by and regulates superoxide anion production during melan-a anchorage blockade The activation of this particular signaling pathway culminates in increased Dnmt expression and global DNA methylation, which in turn may confer selective advantages for cells submitted to a stressful environment
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