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It is widely accepted that DNA methylation profiles are dynamic and prone to modifications in response to normal development and aging, environmental factors, and pathological conditions [4,5]. For example, DNA undergoes progressive global hypomethylation and gene-specific hypermethylation as individuals age, leading to genomic instability or gene-specific suppression [4]. A similar pattern has been observed in cancer where DNA is globally hypomethylated while tumor suppressor genes are hypermethylated compared to normal tissues [6]. Whether these epigenetic patterns are a cause or an outcome of cancer is not entirely understood. Yet, cancer could be prevented through changes in diet or lifestyle that might be attributed to the dynamic and adaptable nature of cancer-associated epigenetic processes, particularly, DNA methylation.

The process of DNA methylation is catalyzed by a group of enzymes called DNA methyltransferases (DNMTs), namely, DNMT1, DNMT2, DNMT3a, DNMT3b, and DNMTL. DNMT1 maintains DNA methylation during cell replication while the rest of the DNMT family, mainly DNMT3a and DNMT3b, are responsible for de novo DNA methylation [9].

DNMTs that are responsible for de novo DNA methylation are highly expresses in developing embryos than adult tissues; yet, there is growing evidence that they play a role in maintaining DNA methylation patterns. For instance, combined genetic deletion or silencing of DNAMT1 and DNMT3b reduced DNA methylation to a greater extent than deleting or silencing either genes alone, supporting the critical role of de novo DNMTs in maintaining DNA methylation [10,11,12]. On the other hand, some studies suggested that DNMT1 is required for de novo DNA methylation. For example, a study by Liang et al. [13] showed that DNMT3a and DNMT3b did not induce de novo DNA methylation efficiently in mouse embryonic stem cells in the absence of DNMT1 gene. Other studies have supported this co-operativity between DNMTs in de novo DNA methylation [14,15,16]. The process of methyl transfer starts by non-specific binding of DNMTs to DNA followed by recognition of specific DNA sites and recruitment of the methyl group donor, S-adnosylmethionine. DNMTs incorporate the donated methyl group into carbon 5 of the cytosine residue followed by a release of the DNMT enzyme and s-adenosylhomocysteine [16].

There is also growing evidence indicating that global hypomethylation may lead to genome instability and DNA breakage [4]. Furthermore, global hypomethylation may be accompanied by loss of imprinting of some oncogenes leading to cancer development such as insulin-like growth factor 2 (IGF-1) in colon cancer [34]. The oncogenes that are linked to cancer and activated via hypomethylation are protease urokinase, mesothelin, cancer-testis genes, claudin4, S100A4, heparinase, and the proopiomelanocortin gene [35]. Global DNA hypomethylation in cancer cells has been suggested to be attributed to one of the following causes: (1) a discoordination between DNA replication in cancer cells and DNMT-1 activity; (2) a natural selection of hypomethylated DNA patterns accompanying overexpression of specific oncogenes or genomic instabilities that facilitate cancer cell growth and expansion; or (3) a consequence of chromatin dysregulation and nuclear disorganization that occur during cancer progression [36].

Micronutrient methyl donors that are involved in the one carbon metabolism and subsequently in DNA methylation. Dietary folate is converted to dihydrofolate (DHF) via the dihydrofolate synthase (DHFS) enzyme then to tetrahydrofolate (THF) by the dihydrofolate reductase (DHFR) enzyme; in both steps, vitamin B3 (B3) acts as a co-factor. THF is then converted to 5,10-methyl THF via the enzyme serine hydroxymethyltransferase (SHMT) that has vitamin B6 (B6) as a coenzyme. This reaction is followed by a reduction of 5,10-methyl THF to 5-methyl THF via the enzyme methylenetetrahydrofolate reductase (MTHFR) and the co-enzyme, vitamin B2 (B2). At the end of this cycle, 5-methyl THF is transformed back to THF by the enzyme 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) that utilizes vitamin B2 as a co-enzyme. The same enzyme, MTR, converts homocysteine (Hcy) to methionine. Betaine acts as an indirect methyl donor for the latter reaction. Methionine, whether it is endogenously synthesized or diet-derived is critical for the synthesis of S-adenosylmethionine (SAM), which acts as a DNA methyltransferase (DNMT) cofactor and a universal methyl-donor for DNA methylation. The enzyme that catalyzes this reaction is methionine adenosyltransferase (MAT). Glycine N-methyltransferase (Glycine N-MT) converts SAM to s-adenosylhomocysteine (SAH), which could be reversibly converted to Hcy via the enzyme SAH hydrolase. Finally, the activated DNMT enzyme will catalyze the transfer of a methyl group to carbon 5 of cytosines in the DNA to produce methylated DNA (mDNA).

Conflicting results regarding the effect of folate status on DNA methylation have been reported. For example, global DNA hypomethylation was reported in three different murine studies in response to either a folate-deficient or a folate-rich diet provided during gestation, lactation, or after weaning [116,117,118]. Another study showed that a folate-deficient diet reduced tumor size in a colorectal cancer mouse model with no effect on global or gene-specific DNA methylation. However, this reduction in tumor size was only observed when the folate-deficient diet was administered after tumor development, and no effect was observed when folate deficiency was induced before tumor development [119]. In a study by Kotsopoulos et al. [120], folate-deficient diet increased DNA methylation in rat liver when administered post weaning and this effect continued through adulthood; no changes in DNA methylation were observed when either a folate-deficient or a folate-rich diet was administered at puberty. These findings may suggest that the dietary level of folate is not the only determinant for DNA methylation status and that other confounding factors might modulate the role of folate as a methyl donor.

Similarly, data from human studies that assessed the contribution of folate deficiency or folate supplementation on cancer risk or progression is inconsistent and varies significantly based on factors such as folate dose, mode of intake (dietary versus supplementary), stage of development during exposure (prenatal versus postnatal), and the pathological status (normal versus neoplastic) of tissues [121,122,123,124]. Other factors such as age, genetic and epigenetic background, alcohol intake, and comorbidities might influence the outcome in folate consumers [125,126].

However, conflicting evidence has emerged, indicating that the mechanisms associated with folate effect on DNA methylation are more complex than previously thought and confounded by other dietary, genetic, or tissue-related factors. For example, a prospective nested case-control study of 331 cases and 662 matched controls in the population-based Northern Sweden Health and Disease Study demonstrated an association between low plasma levels of folate and reduced risk of colon cancer [87]. This study concluded that low circulating levels of folate are protective against colon cancer. Findings from other epidemiological studies were inconsistent; only five out of seven prospective studies [84,88,89,90,91,92,130] and seven out of 11 case-control studies [93,94,95,96,97,98,99,100,101,131,132] have reported a protective effect of folate intake against colon cancer. This discrepancy motivated researchers to conduct meta-analyses of published observational studies to provide an overall estimate of the association between folate intake and colorectal cancer risk. A meta-analysis by Sanjoaquin et al. [133] indicated that dietary folate has a more protective effect on colorectal cancer than supplemental folate. However, confounding factors such as gender, other dietary factors, and alcohol consumption modify the association. A relatively recent meta-analysis reported a lack of association between folate supplementation and total cancer incidence including colorectal cancer, lung cancer, prostate cancer, or breast cancer [134]. Observational studies that assessed the association between folate status and global DNA hypomethylation in cancer patients have also yielded mixed findings. An association between global DNA hypomethylation and increased risk of colon, cervical, and bladder cancer was established in these studies [57,58,59]. However, a role of low folate status (intake or blood levels) in this association could not be consistently found. A significant association between folate status and DNA hypomethylation was reported by Piyathilake et al. [60] in their study of 376 women with cervical intraepithelial neoplasia. Other studies reported either a weak [61] or null association [58,59].

Thus far, studies that measured the association between folate intake and global DNA methylation in cancer have yielded inconsistent results as shown above. This inconsistency could be related to the use of varying doses over varying periods; however, a critical confounding factor that should be considered is the type of methylation assays that were used and what they actually measure [138]. Some of these assays measure DNA methylation status in repetitive elements such as LINE (Long Interspersed Nucleotide Element 1), SINE (Short interspersed nuclear elements), and Alu ( Arthrobacter luteus restriction endonuclease) repeats and others examine differentially methylated regions via methylation-sensitive restriction enzymes [139]. Furthermore, some of the assays cover the whole genome while others cover only a certain percentage of the genome [138]. These assays, in general, have different sensitivity and specificity and are prone to over- or under-estimation errors. Details about global DNA methylation analysis methods are beyond the scope of the current review; the reader is directed to a recent article by Kurdyukov et al. [140] that summarizes and compare these methods in terms of outcomes and appropriateness for specific research questions. However, it is worth mentioning that the correlation among these assays is poor, which could mainly be attributed to the fact that they measure different subsets of DNA sequences in diverse regions of the genome [141]. Distinct methylation profiles of various repetitive DNA elements have been found among different tissues and pathological conditions. Furthermore, loss of DNA integrity in cancer may compromise the accuracy of global DNA methylation assay outcome [142]. Thus, using different global DNA methylation assays to evaluate the effect of folate status on DNA methylation could be the reason behind the reported inconsistent and irreproducible findings. 041b061a72


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