Folate, colorectal cancer and the involvement of DNA methylation

Abstract

Diet is a major factor in the aetiology of colorectal cancer (CRC). Epidemiological evidence suggests that folate confers a modest protection against CRC risk. However, the relationship is complex, and evidence from human intervention trials and animal studies suggests that a highdose of folic acid supplementation may enhance the risk of colorectal carcinogenesis in certain circumstances. The molecular mechanisms underlying the apparent dual modulatory effect of folate on colorectal carcinogenesis are not fully understood. Folate is central to C 1 metabolism and is needed for both DNA synthesis and DNA methylation, providing plausible biological mechanisms through which folate could modulate cancer risk. Aberrant DNA methylation is an early event in colorectal carcinogenesis and is typically associated with the transcriptional silencing of tumour suppressor genes. Folate is required for the production of S-adenosyl methionine, which serves as a methyl donor for DNA methylation events; thereby folate availability is proposed to modulate DNA methylation status. The evidence for an effect of folate on DNA methylation in the human colon is limited, but a modulation of DNA methylation in response to folate has been demonstrated. More research is required to clarify the optimum intake of folate for CRC prevention and to elucidate the effect of folate availability on DNA methylation and the associated impact on CRC biology.Colorectal cancer: Folate: Folic acid: DNA methylation Colorectal cancer (CRC) occurs as a consequence of a complex series of genetic and epigenetic events leading to uncontrolled cell proliferation of malignant cells. Although the genetic events leading to neoplasia are well defined, an appreciation of the importance of epigenetic factors is relatively recent. Aberrant DNA methylation has been recognised as an early event in CRC and has been the focus of considerable research. As with other epigenetic events, DNA methylation is potentially reversible making aberrant DNA methylation in cancer a particularly attractive target for chemotherapeutics and chemoprevention. Diet is known to have a significant impact on risk of CRC and there is some suggestion of an inverse association between folate and CRC risk. Folate is a methyl donor for DNA methylation and consequently DNA methylation has received attention in attempts to elucidate the mechanism whereby folate may modify CRC risk. This review focuses on our current knowledge and understanding of the interaction between folate, CRC and the possible involvement of DNA methylation. Colorectal cancer and its molecular classificationCRC is the third most common cancer in the world, accounting for 10% of all cancers and for approximately 20% of all deaths in the developed world (1) . It is an agerelated disease with peak incidence in the seventh decade of life. The majority of CRC cases are sporadic; however, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer are two forms of early onset hereditary CRC that account for approxi...

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