Abstract
Epigenetic regulation of tumor suppressor genes (TSGs) has been shown to play a central role in melanomagenesis. By integrating gene expression and methylation array analysis we identified novel candidate genes frequently methylated in melanoma. We validated the methylation status of the most promising genes using highly sensitive Sequenom Epityper assays in a large panel of melanoma cell lines and resected melanomas, and compared the findings with those from cultured melanocytes. We found transcript levels of UCHL1, COL1A2, THBS1 and TNFRSF10D were inversely correlated with promoter methylation. For THBS1 and UCHL1 the effect of this methylation on expression was confirmed at the protein level. Identification of these candidate TSGs and future research designed to understand how their silencing is related to melanoma development will increase our understanding of the etiology of this cancer and may provide tools for its early diagnosis.
Highlights
Aberrant epigenetic modifications are a feature of several human diseases, including cancer
There is strong evidence suggesting an inverse relationship between the presence of CpG island methylation and the level of target gene expression [5], this suppression is not always evident. Both hypermethylation of CpG islands located in the promoters of tumor suppressor genes (TSGs) and global hypomethylation seem to play an important role during cancer development
Select candidate genes were followed up using the Epityper assay in a much larger panel of melanoma cell lines, as well as a panel of fresh-frozen melanoma samples, normal melanocyte cultures, and cell lines from other cancer types
Summary
Aberrant epigenetic modifications are a feature of several human diseases, including cancer. While several forms of epigenetic modification are known to exist, so far DNA methylation is the only one shown to directly target DNA and to be frequently aberrant in many tumor types [1,2]. There is strong evidence suggesting an inverse relationship between the presence of CpG island methylation and the level of target gene expression [5], this suppression is not always evident. Both hypermethylation of CpG islands located in the promoters of tumor suppressor genes (TSGs) and global hypomethylation seem to play an important role during cancer development. Often TSGs are not primarily inactivated through mutation or deletion, but rather through targeted CpG island methylation
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