Certain dietary factors, e.g., folate, tea polyphenols, phytoestrogens and isoflavones, curcumin, and resveratrol, are thought to have a chemoprotective effect on the development and the progression of cancer. Many bioactive phytochemicals could potentially alter the expression of key tumor suppressor genes or oncogenes through modulation of DNA methylation and chromatin modification in cancer (Figs. 3 and 4). Bioactive natural compounds appear to act through the decrease of the DNMTs or HDACs gene expression in cancer cell lines and in vivo. In addition, these bioactive dietary factors resulted in modulating tissue levels of miRNAs and their target genes (Shah et al. 2012). Most of the studies were performed in vitro using different cancer cell lines, or in animals, and few studies were intervention studies on human subjects.

The first study indicating this phenomenon showed that maternal diet supplemented with methyl donors, including folate, affected agouti gene expression in Avy/a mice, as a result of retrotransposon hypermethylation, and caused an altered coat phenotype (from a normal yellow to brown) in the genetically identical offspring (Wolff et al. 1998; Waterland and Jirtle 2003). Prenatal famine in humans influences phenotypic changes in offspring caused by DNA methylation changes that persist in the next generation offspring (Tobi et al. 2009; Heijmans et al. 2008). Individuals exposed to severe famine during childhood and adolescence, during the “Dutch Hunger Winter” of 1944–1945, had a decreased risk of developing colorectal cancer and a decreased methylation of a panel of cancer-related genes (Hughes et al. 2009). A reduced DNA methylation of the imprinted insulin-like growth factor 2 (IGF2), persisted six decades later, compared to their unexposed, same-sex siblings (Heijmans et al. 2008). A recent study showed that prenatal dietary supplementation with polyunsaturated fatty acid was associated with higher methylation levels in infants at IGF2/H19 imprinted regions. In addition, in the same study DNA methylation states in infants were associated with maternal body mass index (Lee et al. 2014). The data from these studies indicate that peri-conceptional, prenatal, and early-life conditions can cause epigenetic changes in humans that persist throughout life and could cause cancer.

Folate and other nutrients of one-carbon metabolism, such as vitamin B2, B6, and B12, are the main source of methyl groups or act as coenzymes for the one-carbon metabolism that regulates methyl transfer and DNA synthesis (Anderson et al. 2012). One-carbon metabolism is essential for the synthesis of S-adenosyl-l-methionine (SAM), universal methyl donor for various cellular reactions including DNA methylation and histone methylation (Fig. 3). Extensive evidence has accumulated suggesting that folate deficiency plays a significant role in developing several tumors including cancers of the colorectum, lung, pancreas, esophagus, stomach, cervix, and breast, as well as neuroblastoma and leukemia (Kim 1999). Head and neck cancer patients with the high dietary intake of micronutrients involved in one-carbon metabolism and antioxidant activity (folate, vitamin B12, and vitamin A) and cruciferous vegetable, compared with those in the lowest intake, showed significantly less tumor suppressor promoter methylation, assessed using the Illumina Goldengate Methylation Cancer Panel (Colacino et al. 2012). Low consumption of folate, vitamin A, vitamin B1, potassium, and iron in colorectal cancer patients was associated with the increased promoter hypermethylation of p16, p14 (ARF), or hMLH1 genes (Mas et al. 2007).

Several studies have established a connection between cancer susceptibility and methyl-group metabolism genes, including methylene tetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism and DNA synthesis (Fig. 3). MTHFRC677T genotype was associated with RASSF1A promoter hypermethylation in bladder and oral cancer (Cai et al. 2009; Supic et al. 2011a). Carriers of the 677 T allele of MTHFR gene in patients with colorectal, breast, or lung tumors had global hypomethylation, while patients with methionine synthase 2756GG genotype showed promoter hypermethylation in a large panel of tumor suppressor genes, including p16, p14, hMLH1, MGMT, APC, DAPK, GSTP1, BRCA1, RAR-β 2, CDH1, and RASSF1 (Paz et al. 2002). An interaction between low dietary folate and high alcohol intake in colorectal cancer patients resulted in concordant DNA methylation of tumor suppressor genes (van England et al. 2003). In addition, a significant interaction between heavy drinking and MTHFR667TT genotype, observed in oral cancer patients, resulted in the multiple DNA methylation of tumor suppressor genes (Supic et al. 2011a). These findings indicated that polymorphisms in genes encoding enzymes involved in folate metabolism could be an alternative mechanism that modulates the epigenetic effects of environmental factors. Interaction of folate intake or one-carbon metabolism-related polymorphisms with environmental factors, such as alcohol, could cause changes in DNA methylation (Fig. 3). Future investigations might predict individual susceptibility to cancer and provide science-based recommendations for methyl donors intake, depending on the individual genetic profile exposure for cancer prevention.

Retinoic acid (RA), generated via oxidative conversion from β-carotene absorbed from fruits and vegetables, binds to nuclear retinoic acid receptors (RAR) and heterodimerize with retinoid X receptors (RXR). Subsequently, RA modulates transcription through its response elements in the promoters of target genes, including p21 and AP-1, and exerts the pro-apoptotic actions (Stefanska et al. 2012a). It has been demonstrated that the treatment of noninvasive MCF-7 cells with RA caused the decrease in promoter methylation, consequent increase in the RARβ2 and PTEN (phosphatase and tensin homologue) expression, and the inhibition of breast cancer cell growth (Stefanska et al. 2012b). In the combined treatment, butyrate and RA inhibited proliferation of MCF-7 cells (Andrade et al. 2012). Thus, retinoids have been suggested as a potential epigenetic strategy for the cancer treatment, especially in breast cancers in which RAR β is epigenetically altered.

Vitamin D3, synthesized upon sun exposure and from the diet, binds to vitamin D receptors (VDR). Upon ligand binding, VDR heterodimerize with RXR or RAR, and regulate the transcription of more than a hundred genes, involved not only in calcium and phosphate homeostasis but also in cell proliferation, differentiation, and apoptosis (Chung et al. 2009). Accumulating results revealed the association between vitamin D deficiency and vitamin D-related genes with different cancer types, including breast, prostate, colorectal, oral, lung cancer, melanoma and acute myeloid leukemia (Feldman et al. 2014; Davis and Milner 2011; Zeljic et al. 2012, 2014, Puccetti et al. 2002). In addition, the gene expression of VDR and CYP24A1 gene, coding for 24-hydroxylase, enzyme involved in the vitamin D catabolism, and CYP27B1, coding for 1α-hydroxylase, involved in anabolism, is mediated by epigenetic modifications (Hobaus et al. 2013; Fetahu et al. 2014). In highly invasive MDA-MB-231 cells, exposure to vitamin D3 resulted in hypomethylation and induction of p21, PTEN, and RARβ2 expression (Stefanska et al. 2012a, b). Vitamin D3-mediated promoter demethylation induced the expression of E-cadherin and differentiation of aggressive triple-negative breast cancer cells (Lopes et al. 2012). Dietary vitamin D intake was strongly negatively associated with the Wnt antagonist gene DKK1 methylation in a large cohort of Canadian colorectal carcinoma patients (Rawson et al. 2012). In vitro studies demonstrated that calcitriol [1 alpha,25 Dihydroxyvitamin D(3)], an active metabolite of vitamin D, synergized the pro-apoptotic effect of HDAC inhibitors sodium butyrate (NaB), a natural short-chain fatty acid, and trichostatin A (TSA), a synthetic HDAC inhibitor, in the prostate cancer cells LNCaP, PC-3, and DU-145 (Rashid et al. 2001). Calcitriol inhibited the expression of several HDMs and induced the expression of others (Pereira et al. 2011, 2012). In the colon cancer SW480-ADH cells, calcitriol increased the expression of the HDM Jumonji JMJD3, which upregulated the epithelial-to-mesenchymal transition inducers SNAIL1 and ZEB1, while it downregulated the epithelial proteins, including E-cadherin (Pereira et al. 2011). Novel data indicate that calcitriol exerts its regulatory role via Jumonji C (JmjC) and lysine-specific demethylase (LSD) families of the HDMs (Pereira et al. 2012). In addition, JMJD3 knockdown decreases the expression of miR-200b and miR-200c, two microRNAs targeting ZEB1 RNA (Pereira et al. 2012). In another study, calcitriol upregulation of the expression of miR-627 in the colorectal cancer cells HT-29 and in the mice tumor xenografts led to lower levels of KDM2A, one of the direct targets of miR-627 (Padi et al. 2013). These findings indicate that the antiproliferative effect of calcitriol on the expression of HDMs may well be indirect and could be mediated by microRNAs.

Selenium is an essential micro-element with antioxidant and pro-apoptotic effect (Davis et al. 2000; Davis and Uthus 2002). In the rat colon and liver, selenium deficiency causes global hypomethylation and promoter methylation of p53 and p16gene (Davis et al. 2000). Selenium inhibits DNMT directly interacting with enzyme and indirectly influencing plasma homocysteine level and the SAM:SAH (S-adenosyl-l-homocysteine) ratio in a rat model (Davis and Uthus 2002; Uthus and Ross 2007). In an azoxymethane-induced rat colon carcinogenesis model, combination of selenium and green tea revealed more effective suppression of colorectal oncogenesis than either agent alone. Rats fed the combination diet showed marked reduction of DNMT1 expression and induction of histone H3 acetylation, which were accompanied by restoration of SFRP5, reduced ß-catenin nuclear translocation, Cyclin D1 expression, and cell proliferation (Hu et al. 2013a). In human colon cancer, selenium plays a role in chemoprevention by inhibiting DNMTs, thus suppressing DNA methylation (Fiala et al. 1998). However, in another study treatment of colorectal cancer cells Caco-2 and HCT116 with different concentrations of selenium methylselenocysteine and selenite, either alone or in combination with sulforaphane and iberin, did not impact changes in gene-specific methylation of p16 and ESR1, global methylation of LINE-1 elements, or DNMT expression (Barrera et al. 2013).

Epigallocatechin-3-gallate (EGCG), the major green tea polyphenol catechin, was associated with the lower incidence of a number of cancers (Yang et al. 2001; Tollefsbol 2009). Various findings indicate that EGCG is the potent inhibitor of catechol-O-methyltransferase (COMT) and DNMT activity, in a dose-dependent manner (Lu et al. 2003; Fang et al. 2003). Treatment of human esophageal cells, colon cancer cells, and prostate cancer cells with EGCG inhibits DNMT1 activity in a concentration- and time-dependent manner, leading to the hypomethylation and restored gene expression of p16, RAR β, MGMT, and hMLH1 (Fang et al. 2003). Decreased activity of human telomerase reverse transcriptase (hTERT) in cancer cells is associated with increased DNA methylation of its promoter (Berletch et al. 2008). EGCG treatment inhibits expression of DNMTs leading to the suppression of hTERT, the suppression of cell viability, and the induction of apoptosis in human breast cancer cells (Mittal et al. 2004; Meeran et al. 2011; Berletch et al. 2008). The treatment with natural compounds, EGCG, genistein, withaferin A, curcumin, resveratrol, and guggulsterone, resulted in the decrease of the DNMTs gene expression and the methyl-binding proteins MeCP2 in the breast cancer cell lines (Mirza et al. 2013). EGCG decreased the expression and the levels of DNMTs and HDAC, which resulted in the re-expression of silenced tumor suppressor genes, p16INK4a and p21 in human skin cancer cells, and increased levels of histones acetylation in human skin cancer cells A431 in a dose-dependent manner (Nandakumar et al. 2011).

By miRNA microarray analysis, EGCG treatment was found to modify the expressions of a number of the miRNAs in human hepatocellular carcinoma cell line, as well as miRNA-16 and its anti-apoptotic target Bcl-2, that lead to the induction of apoptosis (Tsang and Kwok 2010). These findings indicate that natural tea polyphenols and EGCG could have the strong potential to reverse the epigenetic changes, without the adverse toxic effects associated with synthetic DNMT or HDAC inhibitors used in chemotherapy.

Caffeic acid and Chlorogenic acid are catechol-structures polyphenols from coffee or black tea that inhibit the DNMTs activity in various human cancer cell lines. Catechol polyphenols may indirectly inhibit DNMT through the increased formation of SAH, during the COMT-mediated O-methylation of these dietary agents, thus changing the SAM:SAH ratio (Lee and Zhu 2006) (Fig. 3). Treatment of human breast cancer cells MCF-7 and MAD-MB-231 with caffeic acid or chlorogenic acid inhibited general DNA methylation in a concentration-dependent manner, and the regional methylation of the RAR β gene promoter (Lee and Zhu 2006).

Curcumin (diferuloylmethane), flavanoid from the rhizome of the plant Curcuma longa, has anticancer activity both in vitro and in vivo (Kunnumakkara et al. 2008). Genome-wide methylation microarrays revealed that in contrast to the generalized, nonspecific global hypomethylation observed with 5-aza-2′-deoxycytidine, curcumin treatment of colorectal cancer cells HCT116, HT29, and RKO caused methylation changes in selected, partially methylated loci, instead of fully methylated CpG sites (Link et al. 2013).

Curcumin upregulates or downregulates histone acetylation, depending on the cell type. In brain cancer cells treated with curcumin, H4 histones are hypoacetylated (Kang et al. 2006), as opposite of prostate cancer cells treated with curcumin, where H3 and H4 histones are hyperacetylated and where curcumin induces apoptosis by the involvement of Bcl-2 family genes and p53 (Shankar and Srivastava 2007). Curcumin inhibited HDACs and HPV expression, upregulated p53, pRb, p21, and p27 in cervical cancer cells SiHa and SiHaR, and resulted in sensitization of cervical cancer cell toward cisplatin, lowering the dose of the chemotherapy (Royt and Mukherjee 2014) In addition, curcumin sensitized tumor cells to the chemotherapeutic drugs cyclophosphamide and paclitaxel through the modulation of PKC, telomerase, NF-kappa B, and HDAC in breast cancer (Royt et al. 2011)

Combined administration of curcumin and emodin, a bioactive factor isolated from the root and rhizome of Rheum palmatum, widely used in traditional Chinese medicine, synergistically inhibited proliferation, survival, and invasion of breast cancer cells through upregulation of miR-34a (Guo et al. 2013). Treatment of colon cancer cells with curcumin and synthetic analogues of curcumin induced apoptosis and reactive oxygen species (ROS) and decreased specificity protein (Sp) transcription factors and Sp-regulated genes, including the epidermal growth factor receptor (EGFR), survivin, bcl-2, cyclin D1, and NFκB, by targeting microRNAs (miR-27a, miR-20a, and miR-17-5p) (Gandhy et al. 2012). The potential effects of curcumin treatment on miRNA expression profiles in a pancreatic cancer cell line showed altered expression, with miRNA-22 upregulated, while miRNA-199a downregulated (Sun et al. 2008). In addition, curcumin reduced the expression of Bcl-2 by upregulating miRNA-15a and miRNA-16 in MCF-7 breast cancer cell line (Yang et al. 2010), thereby inducing apoptosis. Curcumin exerted inhibitory effects on proliferation, migration, and invasion in nasopharyngeal carcinoma by inhibiting the expression of miR-125a-5p, which led to the upregulation of p53 expression (Gao et al. 2014). Another miRNA, MicroRNA-200a/b, was overexpressed after curcumin treatment, and this was accompanied with the increase of apoptotic Bcl-2, Bax, and Bad levels in hepatocellular carcinoma cell lines (Liang et al. 2013). Difluorinated curcumin, a novel analogue of the curcumin, restores tumor suppressor PTEN expression in chemo-resistant colon cancer cells HCT116 and HT-29 through downregulation of key oncomir miR-21 (Roy et al. 2013), which suggests that this bioactive agent could be potentially used in chemotherapy-resistant colorectal cancer treatment.