Folate and DNA methylation.

SIGNIFICANCE: The progressive, dose-dependent, and potentially reversible epigenetic changes observed in cancer present new opportunities in cancer risk modification and prevention using dietary and lifestyle factors. Folate, a water-soluble B vitamin, has been of intense interest because of an inverse association between folate status and the risk of several malignancies (particularly colorectal cancer) and its potential to modulate DNA methylation. Aberrant patterns and dysregulation of DNA methylation are mechanistically related to carcinogenesis. RECENT ADVANCES: The effects of folate on DNA methylation patterns have recently been investigated in two important life stages: pre- and early postnatal life and aging. Recent studies have demonstrated that folate exposure in the intrauterine environment and early life and during the aging process may have profound effects on DNA methylation with significant functional ramifications, including the risk of cancer. CRITICAL ISSUES: Evidence from animal, human, and in vitro studies suggest that the epigenetic effects of folate on DNA methylation are highly complex. The effects are gene and site specific and appear to depend on cell type, target organ, stage of transformation, the degree and duration of folate manipulations, interactions with other methyl group donors and dietary factors, and genetic variants in the folate metabolic pathways. FUTURE DIRECTIONS: The potential for folate to modulate DNA methylation and, thus, modify the risk of cancer in humans is worthy of further investigation. Due to the complex relationship between folate exposure and DNA methylation, more elaborate epidemiological, clinical, and mechanistic studies that determine the clinical, biological, and molecular effects of folate are warranted.