The potential roles of dietary polyphenols and methyl donors in reducing the risk of cancer and their therapeutic applications are being investigated by epigenetics, an important area of emerging study as we attempt to understand the heritable changes in gene function and its role in human disorders (Clemens and Pressman, 2006).
Methylation of DNA and acetylation of histone, the protein component of chromatin, are epigenetic mechanisms linked to cancer. DNA methyltransferases (DNMTs), which utilize S-adenosylmethionine and are modulated, in part, by a group of nutrients called lipotropes (methionine, choline, folate, vitamin B-12), set and preserve DNA methylation patterns. Histone deacetylases (HDACs) affect chromatin structure and transcription. Acetylated histones usually surround actively transcribed genes, which are accompanied by minimal or no methylation. On the other hand, abnormally silenced genes in cancer are associated with deacetylated histones and hypermethylated DNA (Ting et al., 2006). DNMT inhibition, through pharmacologic or genetic means, results in promoter demethylation and gene reactivation (Shames et al., 2007).
Both global DNA hypomethylation and gene-specific DNA hypo- or hypermethylation are present in cancer. Global hypomethylation is associated with early cellular transformation, genomic instability, loss of imprinting (disruption of allele-specific gene expression based on parental origin), and oncogene induction. This process corresponds with extent of disease and metastatic potential in many tumor types (Robertson, 2005). Gene-specific-promoter hypermethylation at CpG (cytosine–phosphate–guanine sequence) islands that are mutational hot spots also occurs early in tumorigenesis, accompanies transcriptional gene silencing, and often coincides with loss of heterozygosity manifesting as complete loss of gene function (Shames et al., 2007). Persistent "stemness" due to DNA hypermethylation and consequent epigenetically heritable repression of genes required for cellular maturation and differentiation may underlie stem cell–driven neoplasia (Ting et al., 2006).
Genes relevant for tumor suppression and invasion, cell-cycle regulation, DNA repair, chromatin remodeling, cell signaling, transcription, and apoptosis are abnormally hypermethylated and silenced by many tumor types (Robertson, 2005). Promoter methylation is also seen in premalignant epithelial and hematopoietic cells infected with oncogenic viruses (Epstein-Barr virus, simian virus 40, hepatitis B virus, hepatitis C virus) and in chronic inflammation with microbial infections (Helicobacter pylori ulcers) and without microbial infections (Barrett’s esophagus due to acid reflux). It increases with aging, carcinogenic exposure, and histologic progression (Shames et al., 2007). In human tumors, hypermethylated tumor suppressor genes include retinoblastoma (Rb), Von Hippel-Lindau, p16INK4a, p15, epithelial cadherin, and MLH1 (McCabe and Caudill, 2005). The expressed proteins are instrumental in an array of cell-cycle, cell-adhesion, cell-transmembrane, and cell-division processes, some of which are calcium dependent.
Dietary phenols exemplified by epigallocatechin 3-gallate (EGCG) from green tea and genistein from soybean can inhibit DNMTs in vitro. This is intriguing because DNMT inhibition is associated with promoter demethylation, resulting in reactivation of silenced genes such as p16IK4a, DNA repair genes MLH1 and GMMT, mammary epithelial cell growth regulatory RARβ, and major detoxifier GSTP1 (glutathione S-transferase π). Inhibition was seen in human esophageal, colon, breast, and prostate cancer cell lines (Fang et al., 2007).
Because most polyphenols have low bioavailability, consumption of these compounds singly may not affect DNA methylation in humans. However, a methyl-donor-deficient diet, such as those with insufficient levels of folate and vitamin B-12, may have clinically adverse consequences that extend beyond simple nutrient deficiencies (Fang et al., 2007). For example, in postmenopausal women with restricted folate intake, global leukocyte DNA hypomethylation was observed, a condition that was reversed upon folate repletion. Serum or red-blood-cell folate was inversely related to DNA methylation in tissue from patients with colorectal adenomas or cancer, cervical dysplasia, and gastric cancer (McCabe and Caudill, 2005). This clinical picture is further complicated by administration of antineoplastic medications (e.g., methotrexate, raloxifene, 5-fluorouracil) and anticonvulsive medications (e.g., phenytoin, valproic acid).
Besides folate repletion and multiple polyphenolic permutations, combined intake of polyphenols with HDAC inhibitors like butyric acid (butter component used for food flavoring) and sulforaphane (potential cancer-fighting antioxidant in cruciferous vegetables) may hold therapeutic value.
Future human studies to identify nontoxic, yet effective combinations of these kinds of food components that reduce the risk of cancer, and to assess their therapeutic potential and possible long-term benefits, are essential.
References for the studies mentioned above are available from the authors.
by Roger Clemens, Dr.P.H.,
Contributing Editor Special Projects Advisor, ETHorn, La Mirada, Calif.
by Sabrina Cheng, M.D.,
FACMG Medical Geneticist Consultant,
University of California, San
Francisco Cancer Risk Program