| While convincing evidence indicates that folate deficiency is inversely related to increased risk of colorectal cancer, the mechanisms by which this occurs have not been established yet. Mediating the transfer of one-carbon moieties is the sole biochemical function known for folate and, in this role, folate may play a role in DNA methylation, an epigenetic correlate in carcinogenesis. In vitro models of folate deficiency (non-transformed and transformed mammalian cells) were used to determine the effects of folate-deficiency on genomic, region and gene-specific methylation patterns, and cellular CpG DNA methyltransferase activity and expression. Folate deficiency induced hypomethylation of genomic DNA, site- and gene-specific methylation alterations, reduced DNA methyltransferase activity, altered DNMT1 and 3a expression and reduced steady state levels of DNMT1 mRNA in a cell-specific manner. These studies provide a mechanistic insight into the role of folate in DNA methylation changes associated with carcinogenesis. |
