Alcohol, DNA methylation, and cancer

Abstract

Cancer is one of the most significant diseases associated with chronic alcohol consumption, and chronic drinking is a strong risk factor for cancer, particularly of the upper aerodigestive tract, liver, colorectum, and breast. Several factors contribute to alcohol-induced cancer development (i.e., carcinogenesis), including the actions of acetaldehyde, the first and primary metabolite of ethanol, and oxidative stress. However, increasing evidence suggests that aberrant patterns of DNA methylation, an important epigenetic mechanism of transcriptional control, also could be part of the pathogenetic mechanisms that lead to alcohol-induced cancer development. The effects of alcohol on global and local DNA methylation patterns likely are mediated by its ability to interfere with the availability of the principal biological methyl donor, S-adenosylmethionine (SAMe), as well as pathways related to it. Several mechanisms may mediate the effects of alcohol on DNA methylation, including reduced folate levels and inhibition of key enzymes in one-carbon metabolism that ultimately lead to lower SAMe levels, as well as inhibition of activity and expression of enzymes involved in DNA methylation (i.e., DNA methyltransferases). Finally, variations (i.e., polymorphisms) of several genes involved in one-carbon metabolism also modulate the risk of alcohol-associated carcinogenesis.

Figure 1

DNA methylation patterns in normal and cancer cells. (a) Repetitive sequences generally are methylated at cytosine nucleotides in normal cells. Global loss of methylation in cancer cells leads to chromosomal instability and activation of endoparasitic sequences. (b) CpG islands in promoter sequences typically are unmethylated in normal cells whereas they can become hypermethylated in cancer cells, leading to transcriptional repression. Examples of genes affected are shown on the right. (c) Similar patterns are seen in CpG island shores, located in front (i.e., upstream) of promoters. (d) CpGs located in gene bodies frequently are methylated in normal cells; this pattern is reversed in cancer cells, leading to initiation of transcription at several incorrect sites.

Figure 2

One-carbon metabolism with a schematic representation of the role of methionine in folate metabolism and transmethylation reactions and steps that are inhibited by alcohol. BHMT: betaine homocysteine methyltransferase; DHF: dihydrofolate; DHFR: dihydrofolate reductase; DNMT: DNA methyltransferase; dTMP: deoxythymidine monophosphate; dUMP: deoxyuridine monophosphate; Hcy: homocysteine; MAT: methionine adenosyl transferase; Met: methionine; MT: methyltransferase; 5-MTHF: 5-methyltetrahydrofolate; 5,10-MTHF: 5,10-methylenete-trahydrofolate; MTHFR: methylenetetrahydrofolate reductase; MTR: methionine synthase; SAH: S-adenosylhomocysteine; SAMe: S-adenosyl-methionine; THF: tetrahydrofolate; TS: thymidylate synthase.