DNA methylation is an important epigenetic mechanism of transcriptional control. DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of cancer. Aberrant methylation of DNA (global hypomethylation accompanied by region-specific hypermethylation) is frequently found in tumor cells. Global hypomethylation can result in chromosome instability, and hypermethylation has been associated with the inaction of tumor suppressor genes. Preclinical and clinical studies suggest that part of the cancer-protective effects associated with several bioactive food components may relate to DNA methylation patterns. Dietary factors that are involved in one-carbon metabolism provide the most compelling data for the interaction of nutrients and DNA methylation because they influence the supply of methyl groups, and therefore the biochemical pathways of methylation processes. These nutrients include folate, vitamin B12, vitamin B6, methionine, and choline. However, looking at individual nutrients may be too simplistic. Dietary methyl (folate, choline, and methionine) deficiency in combination causes decreased tissue S-adenosylmethionine, global DNA hypomethylation, hepatic steatosis, cirrhosis, and ultimately hepatic tumorigenesis in rodents in the absence of carcinogen treatment. Other dietary components such as vitamin B12, alcohol, and selenium may modify the response to inadequate dietary folate.
RobertsonKD, WolffeAP. DNA methylation in health and disease. Nat Rev Genet1: 1119, 2000.
2.
HermanJG, BaylinSB. Gene silencing in cancer in association with promoter hypermethylation. N Eng J Med349: 20422054, 2003.
3.
BirdA. DNA methylation patterns and epigenetic memory. Genes Dev16: 621, 2002.
4.
BrownR, StrathdeeG. Epigenomics and epigenetic therapy of cancer. Trends Mol Med8: S43S48, 2002.
5.
SinghSM, MurphyB, O'reillyRL. Involvement of gene-diet/drug interaction in DNA methylation and its contribution to complex diseases: from cancer to schizophrenia. Clin Genet64: 451460, 2003.
6.
SantiniV, KantarjianHM, IssaJP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med134: 573586, 2001.
7.
BaylinSB, HermanJG, GraffJR, VertinoPM, IssaJ-P. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res72: 141196, 1998.
8.
JonesPA, BaylinSB. The fundamental role of epigenetic events in cancer. Nat Rev Genet3: 415428, 2002.
9.
TsouJA, HagenJA, CarpenterCL, Laird-OffringaIA. DNA methylation analysis: a powerful new tool for lung cancer diagnosis. Oncogene21: 54505461, 2002.
10.
FearonEA, VogelsteinB. A genetic model for colorectal tumorigenesis. Cell61: 759767, 1990.
11.
KimY, MasonJ. Folate, epithelial dysplasia and colon cancer. Proc Assoc Am Physicians107: 218227, 1995.
12.
HanahanD, WeinbergRA. The hallmarks of cancer. Cell100: 5770, 2000.
13.
CostelloJF, PlassC. Methylation matters. J Med Genet38: 285303, 2001.
14.
EstellerM. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene21: 54275440, 2002.
15.
MomparlerRL. Cancer epigenetics. Oncogene22: 64796483, 2003.
16.
EstellerM. Cancer epigenetics: DNA methylation and chromatin alterations in human cancer. In: Llombart-BoschmF, Ed. New Trends in Cancer for the 21st Century. New York: Academic/Plenum Publishers, pp 3949, 2003.
17.
PogribnyIP, JamesSJ, JerniganS, PogribnaM. Genomic hypomethylation is specific for preneoplastic liver in folate/methyl deficient rats and does not occur in non-target tissues. Mutat Res548: 5359, 2004.
18.
SaitoY, KanaiY, SakamotoM, SaitoH, IshiiH, HirohashiS. Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis. Proc Natl Acad Sci U S A99: 1006010065, 2002.
19.
JamesSJ, PogribnyIP, PogribnaM, MillerBJ, JerniganS, MelnykS. Mechanisms of DNA damage, DNA hypomethylation, and tumor progression in the folate/methyl-deficient rat model of hepatocarcinogenesis. J Nutr133: 3740S3747S, 2003.
20.
ScottJM, WeirDG. Folic acid, homocysteine and one-carbon metabolism: a review of the essential biochemistry. J Cardiovas Risk5: 223227, 1998.
21.
RossSA. Diet and DNA methylation interactions in cancer prevention. Ann NY Acad Sci983: 197207, 2003.
22.
ChoiS.-W., MasonJB. Folate status: effects on pathways of colorectal carcinogenesis. J Nutr132: 2413S2418S, 2002.
23.
MillerJW, NadeauMR, SmithJ, SmithD, SelhubJ. Folate-deficiency-induced homocysteinaemia in rats: disruption of S-adenosylmethionine=s co-ordinate regulation of homocysteine metabolism. Biochem J298: 415419, 1994.
24.
De CaboSF, SantosJ, Fernandez-PiquerasJ. Molecular and cytological evidence of S-adenosyl-L-homocysteine as an innocuous undermethylating agent in vivo. Cytogenet Cell Genet71: 187192, 1995.
25.
KimY.-I. Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer?Cancer Epidemiol Biomarkers Prev13: 511519, 2004.
26.
HarnackL, JacobsDRJr., NicodemusK, LazovichD, AndersonK, FolsomAR. Relationship of folate, vitamin B-6, vitamin B-12, and methionine intake to incidence of colorectal cancers. Nutr Cancer43: 152158, 2002.
27.
La VecchiaC, NegriE, PelucchiC, FranceschiS. Dietary folate and colorectal cancer. Int J Cancer102: 545547, 2002.
28.
KoningsEJ, GoldbohmRA, BrantsHA, SarisWH, van den BrandtPA. Intake of dietary folate vitamers and risk of colorectal carcinoma: results from The Netherlands Cohort Study. Cancer95: 14211433, 2002.
29.
FuchsCS, WillettWC, ColditzGA, HunterDJ, StampferMJ, SpeizerFE, GiovannucciEL. The influence of folate and multivitamin use on the familial risk of colon cancer in women. Cancer Epidemiol Biomarkers Prev11: 227234, 2002.
30.
SongJ, MedlineA, MasonJB, GallingerS, KimY1. Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse. Cancer Res60: 54345440, 2000.
31.
KimYI, SalomonRN, Graeme-CookF, ChoiSW, SmithDE, DallalGE, MasonJB. Dietary folate protects against the development of macroscopic colonic neoplasia in a dose responsive manner in rats. Gut39: 732740, 1996.
32.
FangJY, XiaoSD. Folic acid, polymorphism of methyl-group metabolism genes, and DNA methylation in relation to GI carcinogenesis. Gastroenterol38: 821829, 2003.
33.
JacobRA, GretzDM, TaylorPC, JamesSJ, PogribnyIP, MillerBJ, HenningSM, SwendseidME. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J Nutr128: 12041212, 1998.
34.
TraslerJ, DengL, MelnykS, PogribnyI, Hiou-TimF, SibaniS, OakesC, LiE, JamesSJ, RozenR. Impact of Dnmtl deficiency, with and without low folate diets, on tumor numbers and DNA methylation in Min mice. Carcinogenesis24: 3945, 2003.
35.
CurtinK, BiglerJ, SlatteryML, CaanB, PotterJD, UlrichCM. MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev13: 285292, 2004.
36.
GiovannucciE, ChenJ, Smith-WarnerSA, RimmEB, FuchsCS, PalomequeC, WillettWC, HunterDJ. Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev12: 970979, 2003.
37.
SlatteryML, PotterJD, SamowitzW, SchafferD, LeppertM. Methylenetetrahydrofolate reductase, diet and risk of colon cancer. Cancer Epidemiol Biomarkers Prev8: 513518, 1999.
38.
RampersaudGC, KauwellGP, HutsonAD, CerdaJJ, BaileyLB. Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. Am J Clin Nutr72: 9981003, 2000.
39.
BeilbyJ, IngramD, HahnelR, RossiE. Reduced breast cancer risk with increasing serum folate in a case-control study of the C677T genotype of the methylenetetrahydrofolate reductase gene. Eur J Cancer40: 12501254, 2004.
40.
ErgulE, SazciA, UtkanZ, CanturkNZ. Polymorphisms in the MTHFR gene are associated with breast cancer. Tumour Biol24: 286290, 2003.
41.
FreudenheimJL, BonnerM, KrishnanS, AmbrosoneCB, GrahamS, McCannSE, MoysichKB, BowmanE, NemotoT, ShieldsPG. Diet and alcohol consumption in relation to p53 mutations in breast tumors. Carcinogenesis25: 931939, 2004.
42.
MenvielleG, LuceD, GoldbergP, BugelI, LeclercA. Smoking, alcohol drinking and cancer risk for various sites of the larynx and hypopharynx. A case-control study in France. Eur J Cancer Prev13: 165172, 2004.
43.
VisapaaJP, GotteK, BenesovaM, LiJ, HomannN, ConradtC, InoueH, TischM, HorrmannK, VakevainenS, SalaspuroM, SeitzHK. Increased cancer risk in heavy drinkers with the alcohol dehydrogenase 1C*1 allele, possibly due to salivary acetaldehyde. Gut53: 871876, 2004.
44.
Dal MasoL, La VecchiaC, PoleselJ, TalaminiR, LeviF, ContiE, ZambonP, NegriE, FranceschiS. Alcohol drinking outside meals and cancers of the upper aero-digestive tract. Int J Cancer102: 435437, 2002.
45.
MunakaM, KohshiK, KawamotoT, TakasawaS, NagataN, ItohH, OdaS, KatohT. Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. J Cancer Res Clin Oncol129: 355360, 2003.
46.
van EngelandM, WeijenbergMP, RoemenGM, BrinkM, de BruineAP, GoldbohmRA, van den BrandtPA, BaylinSB, de GoeijAF, HermanJG. Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. Cancer Res63: 31333137, 2003.
47.
ChoiSW, StickelF, BaikHW, KimYI, SeitzHK, MasonJB. Chronic alcohol consumption induces genomic but not p53-specific DNA hypomethylation in rat colon. J Nutr129: 19451950, 1999.
WallworkJC, DuerreJA. Effect of zinc deficiency on methionine metabolism, methylation reactions and protein synthesis in isolated perfused rat liver. J Nutr115: 252262, 1985.
50.
RowlingMJ, McMullenMH, SchalinskeKL. Vitamin A and its derivatives induce hepatic glycine N-methyltransferase and hypomethylation of DNA in rats. J Nutr132: 365369, 2002.
51.
DavisCD, UthusEO, FinleyJW. Dietary selenium and arsenic affect DNA methylation in vitro in Caco-2 cells and in vivo in rat liver and colon. J Nutr13029032909, 2000.
52.
HaliwellB. Vitamin C and genomic stability. Mutat Res475: 2935, 2001.
53.
UthusEO. Estimation of safe and adequate daily intake for arsenic. In: MertzW, AbernathyCO, OlinSS, Eds. Risk Assessment of Essential Elements. Washington, DC: ILSI Press, pp 273282, 1994.
Lyn-CookBD, BlannE, PaynePW, BoJ, SheehanD, MedlockK. Methylation profile and amplification of proto-oncogenes in rat pancreas induced with phytoestrogens. Proc Soc Exp Biol Med208: 116119, 1995.
56.
TsujiuchiT, TsutsumiM, SasakiY, TakahamaM, KonishiY. Hypomethylation of CpG sites and c-myc gene overexpression in hepatocellular carcinomas, but not hyperplastic nodules, induced by a choline-deficient L-amino acid-defined diet in rats. Jpn J Cancer Res90: 909913, 1999.
57.
OkojiRS, YuRC, MaronpotRR, FroinesJr.. Sodium arsenite administration via drinking water increases genome-wide and Ha-ras DNA hypomethylation in methyl-deficient C57BL/6J mice. Carcinogenesis23: 777785, 2002.
58.
JhaveriMS, WagnerC, TrepelJB. Impact of extracellular folate levels on global gene expression. Mol Pharmacol60: 12881295, 2001.
59.
BhaveMR, WilsonMJ, PoirierLA. c-H-ras and c-K-ras gene hypomethylation in the livers and hepatomas of rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis9: 343348, 1988.
60.
ZapisekWF, CroninGM, Lyn-CookBD, PoirierLA. The onset of oncogene hypomethylation in the livers of rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis13: 18691872, 1992.
61.
SohnKJ, StempakJM, ReidS, ShirwadkarS, MasonJB, KimYI. The effect of dietary folate on genomic and p53-specific DNA methylation in rat colon. Carcinogenesis24: 8190, 2003.
62.
FangMZ, WangY, AiN, HouZ, SunY, LuH, WelshW, YangCS. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res63: 75637570, 2003.
63.
DavisCD, UthusEO. Dietary folate and selenium affect dimethylhydrazine-induced aberrant crypt formation, global DNA methylation and one-carbon metabolism in rats. Nutr133: 29072914, 2003.
64.
TakiguchiM, AchanzarWE, QuW, LiG, WaalkesMP. Effects of cadmium on DNA-(cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformationExp Cell Res286: 355365, 2003.
65.
PoirierLA, VlasovaTI. The prospective role of abnormal methyl metabolism in cadmium toxicity. Environ Health Perspect110: 793795, 2002.
66.
FurumaiR, MatsuyamaA, KobashiN, LeeKH, NishiyamaM, NakajimaH, TanakaA, KomatsuY, NishinoN, YoshidaM, HorinouchiS. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res62: 49164921, 2002.
67.
LuZ, YangY-T, ChenC-S, DavisM, ByrdJC, EtertonMR, UmarA, ChenC-S. Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors. J Med Chem47: 467474, 2004.
68.
GriseriP, PatroneG, PuppoF, RomeoG, RavazzoloR, CeccheriniI. Rescue of human RET gene expression by sodium butyrate: a novel powerful tool for molecular studies in Hirschsprung disease. Gut52: 11541158, 2003.
69.
LeeYW, KleinCB, KargacinB, SalnikowK, KitaharaJ, DowjatK, ZhitkovichA, ChristieNT, CostaM. Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: a new model for epigenetic carcinogens. Mol Cell Biol15: 25472557, 1995.
70.
BrodayL, PengW, KuoMH, SalnikowK, ZorodduM, CostaM. Nickel compounds are novel inhibitors of histone H4 acetylation. Cancer Res60: 238241, 2000.
71.
SteinmetzKL, PogribnyIP, JamesSJ, PitotHC. Hypomethylation of the rat glutathione S-transferase pi (GSTP) promoter region isolated from methyl-deficient livers and GSTP-positive liver neoplasm. Carcinogenesis19: 14871494, 1998.
72.
BrunaudL, AlbertoJM, AyavA, GerardP, NamourF, AntunesL, BraunM, BronowickiJP, BreslerL, GueantJL. Effects of vitamin B12 and folate deficiencies on DNA methylation and carcinogenesis in rat liver. Clin Chem Lab Med41: 10121019, 2003.
73.
CooneyCA, DaveAA, WolffGL. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr132: 2393S2400S, 2002.
74.
WaterlandRA, JirtleRL. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition20: 6368, 2004.
75.
PufuleteM, Al-GhnaniemR, LeatherAJ, ApplebyP, GoutS, TerryC, EmeryPW, SandersTA. Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology124: 12401248, 2003.
