Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis

Abstract

Inappropriate diet may contribute to one third of cancer deaths. Folates, a group of water-soluble B vitamins present in high concentrations in green, leafy vegetables, maintain DNA stability through their ability to donate one-carbon units for cellular metabolism. Folate deficiency has been implicated in the development of several cancers, including cancer of the colorectum, breast, ovary, pancreas, brain, lung and cervix. Generally, data from the majority of human studies suggest that people who habitually consume the highest level of folate, or with the highest blood folate concentrations, have a significantly reduced risk of developing colon polyps or cancer. However, an entirely protective role for folate against carcinogenesis has been questioned, and recent data indicate that an excessive intake of synthetic folic acid (from high-dose supplements or fortified foods) may increase human cancers by accelerating growth of precancerous lesions. Nonetheless, on balance, evidence from the majority of human studies indicates that dietary folate is genoprotective against colon cancer. Suboptimal folate status in humans is widespread. Folate maintains genomic stability by regulating DNA biosynthesis, repair and methylation. Folate deficiency induces and accelerates carcinogenesis by perturbing each of these processes. This review presents recent evidence describing how these mechanisms act, and interact, to modify colon cancer risk.

Gene promoter methylation in colorectal cancer and healthy adjacent mucosa specimens

“…5 There is consensus in the literature indicating that individuals who habitually consume the greatest quantities of folate, or who have the highest concentrations of blood folate, are at decreased risk for the development of CRC. 6,7 However, folate derivatives are cofactors in nucleotide synthesis and high levels of the vitamin could therefore promote the proliferation of rapidly dividing cells. 6,7 Indeed, the current opinion is that higher folate intake is protective against CRC development in nearly all circumstances except for those individuals who consume an excessive amount of the vitamin and have existing neoplastic lesions.…”

“…6,7 However, folate derivatives are cofactors in nucleotide synthesis and high levels of the vitamin could therefore promote the proliferation of rapidly dividing cells. 6,7 Indeed, the current opinion is that higher folate intake is protective against CRC development in nearly all circumstances except for those individuals who consume an excessive amount of the vitamin and have existing neoplastic lesions. 6,7 Given its pivotal role in DNA methylation processes, onecarbon metabolism has been largely investigated as a potential modulator of DNA methylation in CRC.…”

Epigenetic modifications and human pathologies: cancer and CVD

“…Severe and prolonged folate depletion in rodents induces global DNA hypomethylation in the liver and certain regions of the colon (49)(50)(51) ). Moderate folate deficiency does not consistently induce global DNA hypomethylation in blood, liver and colon, despite a significant depletion in blood and tissue folate and liver SAM (52)(53)(54) . Lymphocyte DNA is hypomethylated in women made experimentally folate deficient over several weeks (55,56) and low-dietary folate intake (< 200 mg/d) correlates with hypomethylation of long-interspersed nucleotide element repeats (LINE-1; used as an indicator of global DNA methylation) in human colon tumours (57) .…”

Glutamine at focus: versatile roles in cancer

“…Recently, the p53-family member p73 has been linked to play an important role in the serine biosynthesis, under metabolic stress [121]. The glycine generated by the serine metabolism is related to maintain DNA stability and normal methylation patterns [122,123]. Related effects of folate metabolism were reported by Farber and Diamond in 1948, after treatment of children with AML by the treatment with 4-aminopteroylglutamic acid, leading to a temporary remission of leukemia [124].…”