Epigenetic mechanisms in anti-cancer actions of bioactive food components--the implications in cancer prevention

Abstract

The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by both genetic and epigenetic modifications. Epigenetics refers to the changes in gene expression programming that alter the phenotype in the absence of a change in DNA sequence. Epigenetic modifications, which include amongst others DNA methylation, covalent modifications of histone tails and regulation by non-coding RNAs, play a significant role in normal development and genome stability. The changes are dynamic and serve as an adaptation mechanism to a wide variety of environmental and social factors including diet. A number of studies have provided evidence that some natural bioactive compounds found in food and herbs can modulate gene expression by targeting different elements of the epigenetic machinery. Nutrients that are components of one-carbon metabolism, such as folate, riboflavin, pyridoxine, cobalamin, choline, betaine and methionine, affect DNA methylation by regulating the levels of S-adenosyl-L-methionine, a methyl group donor, and S-adenosyl-L-homocysteine, which is an inhibitor of enzymes catalyzing the DNA methylation reaction. Other natural compounds target histone modifications and levels of non-coding RNAs such as vitamin D, which recruits histone acetylases, or resveratrol, which activates the deacetylase sirtuin and regulates oncogenic and tumour suppressor micro-RNAs. As epigenetic abnormalities have been shown to be both causative and contributing factors in different health conditions including cancer, natural compounds that are direct or indirect regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy.

Figure 1

One-carbon metabolism. This network of biochemical reactions is essential for synthesis of S-adenosyl-L-methionine (SAM) that is the unique methyl donor for various methylation reactions including DNA and histone methylation. The crucial co-enzymes and intermediary compounds involved in the one-carbon metabolism comprise bioactive food components such as folate, pyridoxine (vitamin B6), riboflavin (vitamin B2) and cobalamin (vitamin B12), as well as methionine and choline. Abbreviations: 5,10-MTHF, 5,10-methylenetetrahydrofolate; 5-CH3-THF, 5-methyltetrahydrofolate; BHMT, betaine homocysteine methyltransferase; CBS, cystathionine-β-synthase; DHFR, dihydrofolate reductase; DNMTs, DNA methyltransferases; GNMT, glycine N-methyltransferase; HMTs, histone methyltransferases; MAT, methionine adenosyltransferase; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; MTs, methyltransferases; SAH, S-adenosyl-L-homocysteine; SAHH, S-adenosyl-L-homocysteine hydrolase; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate.

Figure 2

Scheme demonstrating mechanisms used by natural compounds to drive changes in the epigenome. (A) Reciprocal interconnections between all the components of the epigenome: DNA methylation, histone modifications and non-coding RNAs. Compounds driving changes in DNA methylation patterns may have indirect effects on other epigenetic components and vice versa. (B) PCNA is crucial for DNMT1 activity during replication when DNA methylation pattern is copied from a parental to a daughter DNA strand. p21 competes with DNMT1 for the same binding site on PCNA, which impairs DNMT1 activity. Compounds that lead to an increase in p21 expression can affect DNA methylation. Several natural agents such as curcumin and EGCG bind to the DNMT1 catalytic domain and impair its enzymatic activity. (C) AP-1 binding sites have been identified within the DNMT1 regulatory region. Compounds that inhibit the MAPK signalling pathway by, for example, up-regulating PTEN can attenuate DNMT1 transcription. (D) Compounds with a catechol group are excellent substrates for catechol-O-methyltransferase (COMT) that catalyzes their methylation. The COMT-mediated methylation reaction results in depletion of the methyl donor SAM and formation of SAH, which is a potent feedback inhibitor of DNA methylation.