Environment, diet and CpG island methylation: Epigenetic signals in gastrointestinal neoplasia
Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK. <>Food and Chemical Toxicology (Impact Factor: 2.9). 05/2008; 46(4):1346-59. DOI: 10.1016/j.fct.2007.09.101
The epithelial surfaces of the mammalian alimentary tract are characterised by very high rates of cell proliferation and DNA synthesis, and in humans they are highly susceptible to cancer. The role of somatic mutations as drivers of carcinogenesis in the alimentary tract is well established, but the importance of gene silencing by epigenetic mechanisms is increasingly recognised. Methylation of CpG islands is an important component of the epigenetic code that regulates gene expression during development and normal cellular differentiation, and a number of genes are well known to become abnormally methylated during the development of tumours of the oesophagus, stomach and colorectum. Aberrant patterns of DNA methylation develop as a result of pathological processes such as chronic inflammation, and in response to various dietary factors, including imbalances in the supply of methyl donors, particularly folates, and exposure to DNA methyltransferase inhibitors, which include polyphenols and possibly isothiocyanates from plant foods. However the importance of these environmental interactions in human health and disease remains to be established. Recent moves to modify the exposure of human populations to folate, by mandatory supplementation of cereal foods, emphasise the importance of understanding the susceptibility of the human epigenome to dietary and other environmental effects.
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- "The antifolate character of TMECG could explain its anticancer action, since folate is indispensable for normal DNA synthesis. Further, a shortage of folate can cause DNA hypomethylation which, in turn, is found in many types of cancers and presumably triggers proto-oncogene activation[87,88]. Piyaviriyakul and co-workers demonstrated that EGCG derivatives, 6-(5-aminopentyl)-5,7-dideoxyepigallocatechin gallate (cis-APDOEGCG) (43) and 6-(5-aminopentyl)-5,7-dideoxy gallocatechin gallate (trans-APDOEGCG) (44), exhibited greater potency as angiogenesis suppressors in HUVEC cells compared to the parent compound. "
ABSTRACT: As evidenced by a growing number of respective clinical trials, a promising and increasingly valued approach to cancer prevention is chemoprevention which is based on using synthetic, semisynthetic, or natural compounds with the aim of preventing, delaying, arresting, or reversing carcinogenesis. Research carried out in the last two decades indicates that natural polyphenols isolated from plants (as well as their derivatives and synthetic analogs) exhibit pleiotropic actions toward cancer cells and therefore they could be used in both cancer prevention and therapy. This review discusses selected covalent modifications of polyphenols as a means for increasing their anticancer potential in relation to the parent compounds. The modifications include hydroxylation, methylation, acylation, and galloylation, among others. They were demonstrated to enhance cytotoxic, pro-oxidant, antiproliferative, proapoptotic, proauthophagic, and antimigratory activities of phenolics toward various cancer cell lines in vitro. Importantly, some derivatives proved to suppress tumor growth and metastasis in animal models more strongly than the parent compounds. Some of the above-mentioned covalent modifications were also shown to increase absorption and tissue distribution of tested phenolic compounds in vivo. Anticancer clinical trials with polyphenol derivatives therefore seem warranted.
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- "DNA methylation, which occurs primarily in the C5 position of the cytosine ring in 5=-to 3=-oriented CG dinucleotides (CpG), affects gene expression in many biological processes such as differentiation, genomic imprinting , and DNA mutation and repair  . DNA hypermethylation , usually occurring at promoter CpG islands, is a major epigenetic mechanism for silencing the expression of genes  and is tightly regulated by three different DNA methylases involved in de novo and maintenance methylation during replication  . Other DNA methyl group transfer-related enzymes are demethylases, which act by demethylating DNA during differentiation . "
ABSTRACT: We assessed the impact of high serum folate concentration on erythrocyte S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) concentrations, SAM/SAH ratio, CpG methylation levels across the promoter region of the extracellular superoxide dismutase (ec-SOD) gene, and ec-SOD activity in healthy men. Serum folate levels were measured in 111 subjects who were categorized in quintiles according to their folate status. Subjects located at the lowest, middle, and upper quintiles were selected for assessment of SAM and SAH by high-performance liquid chromatography, C677T genotype of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, ec-SOD methylation of CpG sites in lymphocytes genomic DNA by bisulfate treatment, and ec-SOD activity by a chemical assay. Sixteen subjects were in the lowest serum folate quintile (<23.6 nmol/L), 17 in the middle (>34-<42 nmol/L), and 14 in the highest (>45nmol/L). SAM concentration was higher in the upper than in the middle and lowest quintiles (5.57 +/- 1.58, 2.52 +/- 0.97, 2.29 +/- 1.2 micromol/L; P < 0.0001). SAH concentration was higher in the upper compared with the lowest quintile (0.76 +/- 0.24 versus 0.52 +/- 0.23 micromol/L, P < 0.001). There were no differences in the SAM/SAH ratio, ec-SOD activity, methylation status of CpG sites of the ec-SOD gene, and TMTHFR C677T genotype between groups. Serum folate concentrations in the highest quintile among healthy humans are associated with increased erythrocyte SAM and SAH concentrations, but not with SAM/SAH ratio or with methylation levels of CpG sites across the promoter region of the ec-SOD gene. Further research is required to determine if these findings are beneficial or harmful.
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ABSTRACT: The term epigenetics describes mecha- nisms inducing changes in gene expres- sion or phenotype not caused by altera- tions in the underlying DNA sequence. Compared to the genome, which is al- most identical in different cell types and consistent throughout life, the epige- nome is varying between different cell types as well as over the course of a life- time (1). Twin studies demonstrated, that identical twin pairs, being epigenetically indistinguishable at early life exhibit stri- king differences in epigenetic patterns, as over time they accumulated signifi cant differences in global levels of epigenetic marks (2). It is becoming increasingly evident that distinct nutritional stimuli are able to alter the DNA confi guration at critical ontoge- nic stages as well as that these alterna- tions persist in gene expression. Occur- ring in the gametes these changes may be heritable and they are affected from
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