DNA Methylation
4/20/2017
It is well-known that genome instability plays a significant role in cancer. Genetic stability is affected by DNA methylation. Epigenomes may play a role in DNA modification without changing the sequence of DNA. Methyl donors are substrates from a complex metabolic pathway affected by nutrients, environment, and lifestyle factors. Metabolism disorders of nutrients due to polymorphisms may influence the risk of lung cancer. Nutrigenomics provides valuable research in identifying nutrient effects on the genome. Identification of phenotypes utilizing epigenetics could offer therapeutic targets for nutrition in reducing the occurrence of lung cancer.
Lung cancer is the leading cause of death from cancer. In 2014, diagnoses of 224,201 new cases, of these diagnosis statistics showed that 83.4% of these individuals would be dead in five years (Tastekin et al., 2015). Molecular-level research seeks to find useful markers to determine a person’s susceptibility to lung cancer. Studies show that people can smoke the same number of cigarettes, the same amount of time, and lung cancer does not evolve for all. Disorders of the metabolism of nutrients, environmental factors, and genetic polymorphisms may affect the risks of those who do get lung cancer. Dysregulation of DNA methylation is thought to be a factor in the risk of lung cancer.
Evidence shows that DNA methylation is affected by nutritional and environmental factors. One carbon metabolism is a cyclical cellular process that generates methyl donors for DNA methylation. The necessary dietary micronutrients for one-carbon metabolism include methionine which is regulated by folate, choline, betaine which is an active metabolite of choline, and B vitamins (Anderson, Sant, & Dolinoy 2012). Lifestyle can negatively affect the epigenome through smoking, consuming alcohol, exposure to UV light, and factors that create oxidative stress. Endocrine-disrupting chemicals (EDCs), Bisphenol A (BPA), DTT, and other insecticides dysregulate DNA methylation.
The DNA sequence is usually permanent, but epigenetics provides a potential pathway for molecular modifications to DNA and chromatin without altering the DNA sequence. External effects on the epigenome have the ability to cause DNA methylation, chromatin remodeling, histone tail modifications, and non-coding RNA (ncRNA) and microRNA (miRNA) gene regulation. DNA methylation was the first epigenetic variation linked to cancer and the focus of this paper. Hypomethylation occurs when a methyl group is lost from the nucleotide, this contributes to genome instability. Hypermethylation, which is linked to the epigenetic layers of DNA methylation causes the inactivation of tumor suppressor genes (Sales, Pelegrini, & Goersch 2014).
Nutrition through natural bioactive components affects DNA methylation (Romani, Pistillo, & Banilli 2015). The study of a particular diet in relation to its effect on the expression and protection of genes is called nutrigenomics. Avoiding carcinogens is virtually impossible, but consuming protective bioactive micronutrients may modulate the risk of cancer (Elsamanoudy, Neamat-Allah, Mohammad, Hassanien, & Nada, 2016).
Genetic factors involved in cancer include DNA instability and gene alterations. These factors are affected by nutrient-dependent interactions at the genetic, molecular, protein production, and metabolic profile levels (Elsamandoy et al., 2016). Bioactive nutrients maintain healthy cellular activity, have an impact on the neoplastic transition of normal cells to cancerous cells, and alter the behavior of the neoplasm. Dietary factors affect the cell-cycle checkpoints and play a role in reducing the progression of a tumor. Niacin (B3), folate (B9), and B12 affect the stability of nuclear and mitochondrial genomes (Ferguson et al. 2015). Polyphenols repress oncogenes and activate tumor suppressor genes. Polyphenols, Vitamin B, choline, and methionine affect DNA methylation reducing the risk for lung cancer.
A study by Romani, Pistillo, & Banelli (2015) hypothesized that epigenetics is the key to transforming genetic information into phenotype. In 2004 it was discovered that histone methylation was reversible. The researchers theorized that the reversibility of this information would make the phenotypes a target for therapeutic interventions. The researchers found that tumor suppressor genes are deregulated by the carcinogens in cigarettes. They also discovered several other environmental factors that affected genome stability. EDCs interfere with the endocrine system by mimicking natural molecules. EDCs are transgenerational. Epoxy resin coating in canned foods releases BPA. BPA alters the expression of genes through histone methylation, DNA methylation, and miRNA expression. DTT and other insecticides can alter DNA methylation for three generations.
Li (2012) found that the bioactive components of polyphenols repress oncogenes and activate tumor suppressor genes. It is believed that these dietary components have a direct inhibitory effect on epigenetic enzymes including DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) that affect DNA methylation status.
A study by Sales, Pelegrini, and Goersch (2014) defines nutrigenomics as the combined study of biochemistry, physiology, nutrition, genomics, proteomics, metabolomics, transcriptomics, and epigenomic to understand the relationship between genes and nutrients at the molecular level. The interaction between genes and nutrients determines the ability of the binding control of RNA polymerase, which is an enzyme that produces transcript RNA. Folic acid provides a stable amount of deoxyribonucleotides for DNA replication in folate metabolism. Deoxyribonucleotide is a cofactor for enzymes associated with the biosynthesis of nucleotide and thymidylate (proteins in RNA molecules). Deoxyribonucleotides is also a universal donor methyl and DNA methylation reaction.
A study by Ferguson et al. (2015) focused on five priority targets against genomic instability and nutritional factors that can prevent genomic instability. Five priority targets against genomic instability are prevention of DNA damage, enhancement of DNA repair, targeting deficient DNA repair, impairing centrosome clustering, and inhibition of telomerase activity. The poly ADP ribose polymerase (PARP) family of enzymes plays a significant role in DNA repair. A deficiency in niacin impairs the function of PARP. Folate deficiency in connection with low levels of B6 and B12 leads to chromosome breaks, deletions of mitochondrial DNA (mtDNA), and may also lead to reduced telomere length.
A clinical study conducted by Swartz et al. (2013) found that dietary folate status may be affected by genes that compromise the folate metabolic pathway. The researchers found that low folate status is associated with lung cancer. Low folate increases DNA strand breaks and reduces DNA repair. A diet high in folate showed a 40% reduction in lung cancer risk among current and former smokers. The researchers also found that elevated levels of B6 and methionine may offer different levels of protection against lung cancer.
Swartz et al. (2013) found that folate genes implicated in lung cancer risk include methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TYMS), serine hydroxymethyltransferase 1 (SHMT1), and cystathionine B-synthase (CBS). Other suspected genes in lung cancer risk include methionine synthase reductase (MTR) and methionine synthase reductase (MTRR). Methionine syntheses controlled by MTRR uses methionine as a methyl donor for DNA methylation. Disruption in this process can cause chromosome instability and DNA hypomethylation and then cancer. TYMS is an essential enzyme utilized in the production of thymidine. Thymidine is a critical nucleotide used in DNA synthesis and repair. Interactions of MTRR with choline, which is a macronutrient that has a similar function as vitamin B, and riboflavin have shown a decreased risk of lung cancer among never smokers.
A clinical study by Tastekin et al. (2015) focused on the effects of homocysteine (Hcy), B12, and folates in relation to lung cancer. A clinical study was conducted on newly diagnosed lung cancer patients analyzing the relationship of B12, folate, and Hcy to lung cancer. The researchers discovered that high plasma homocysteine and low folate could be related to lung cancer. There was no significant difference in the levels of B12 between participants with lung cancer and the control group.
It is well known that cancer is caused by genome instability. Environmental and lifestyle factors can have adverse effects on DNA methylation. Dysregulation of DNA methylation has been shown to increase the risk of lung cancer. The environment can affect the epigenome as exogenous micro RNA (miRNA) sequences, enter cells, and exert their biological effect (Romani, Pistillo, & Banelli 2015). miRNAs are involved in cell growth, differentiation, apoptosis, maintenance of cell identity, and deregulated in cancer. Smoking, alcohol consumption, UV light exposure, and oxidative stress interfere with DNA methylation. BPA alters the expression of genes through histone methylation, DNA methylation, and miRNA expression. One carbon metabolism is a cyclical cellular process that generates methyl donors for DNA methylation. One carbon metabolism is the reaction of several enzymes in the presence of dietary micronutrients. SAM is the primary methyl donor for DNA methylation. Foods and nutrients that play a role in the methyl-making pathway can be seen below.
There are more than 25,000 bioactive food ingredients, 500 of these have proved to be proponents that play a role in cancer, modifying gene expression by the nutrients that regulate DNA transcription. Bioactive components of polyphenols, such as epigallocatechin-3-gallate (EGCG) from green tea, isoflavone, genistein in soy products, isothiocyanate and sulforaphane (SFN) in cruciferous vegetables, and resveratrol from grapes and berries have been shown effective in influencing gene expression through DNA methylation (Li 2012).
DNMT is a family of enzymes that catalyze the transfer of a methyl group from SAM to specific sites on the DNA. Studies show that nutrients play a vital role in the methylation of organic substrates and can influence DNA methylation by changing the availability of methyl donors by modulation of DNMTs activity. Folic acid, vitamin B6, and B12 are essential for one-carbon metabolism. An unbalanced intake of these nutrients can reduce the bioavailability of SAM and cause abnormal DNA methylation. SAM metabolizes compounds from food. These compounds include folic acid (B9 - found in dark green leafy veggies, asparagus, broccoli), pyridoxine (B6 - found in chickpeas, salmon, tuna, beef liver, chicken breast), cobalamin (B12 -found in dairy and meat), riboflavin (B2 - found in beef liver, lamb, milk, yogurt, mushrooms, spinach, almonds, choline found in egg yolk and legumes), and methionine (an amino acid important in angiogenesis - found in egg whites, free-range chickens, wild-caught fish, and turkey). Studies show that deficiencies in micronutrients (folic acid, B12, B6, and others) create the same effect on DNA as radiation exposure which leads to DNA double-strand breakage and oxidative lesions. DNA mutilation which uses methionine is necessary for the interference of DNA replication in cancer. Methionine is a product of folic acid through many chemical processes of catabolism and synthesis (Sales, Pelegrini, and Goersch 2014). Inflammation, immune system evasion, or apoptosis resistance are effects of genomic instability that create an opportunity for cancer survival. Cancer cells can be prevented from replicating, evading the immune system, and anti-growth signaling by prevention and treatment of genomic instability. Vitamin B has a positive effect on the dysregulation of the metabolic pathway that increases the progression of cancer (Ferguson et al., 2015).
Studies show that nutrients play a vital role in the methylation of organic substrates and can influence DNA methylation by changing the availability of methyl donors by modulation of DNMTs activity. Folic acid, vitamin B6, and B12 are essential for one-carbon metabolism. An unbalanced intake of these nutrients can reduce the bioavailability of SAM and cause abnormal DNA methylation. DNMT is a nutrient that catalyzes the transfer of a methyl group from SAM to specific sites on the DNA. SAM metabolizes compounds from food; folic acid, B6, B12, B2, choline, and methionine.
Tastekin et al. (2015) found that high levels of Hcy and low levels of folate are associated with lung cancer. The researchers believe that Hcy could be used as a marker for the determination of lung cancer or its recurrence. Hcy is a non-protein amino acid that biosynthesizes, utilizing B6 as a cofactor, and recycles to the essential amino acid methionine. Hcy speeds up oxidation and free radical production. The bioactive form of pyridoxal-5-phosphate (PLP), is necessary for the catabolism of Hcy. Pyridoxal kinase (PDXK), an enzyme that activates B6 by converting it to PLP is a potential therapeutic marker in patients with lung cancer. Folate and B6 are part of the process of DNA methylation and the synthesis of purines and thymidylate for DNA synthesis. Folate deficiency reduces purine synthesis and decreases the cellular concentration of thymine. Uracil (U) is inserted into DNA when thymine is not available, causing an increase in DNA breaks (Denny, Bay, & Ferguson 2010). The deficiency regulates DNA methylation by shifting cellular levels of SAM which controls gene expressions. DNA hypomethylation is evident when comparing healthy and folate-deficient tissue. Epidemiological, clinical, and experimental studies show that folate deficiency increases the risk of several cancers, including lung.
Genetic stability is a very complicated process that is affected by many different aspects, internal and external. Genetic instability causes cancer. Dysregulated DNA methylation was the first epigenomic associated with cancer. Production of the methyl donor, SAM, requires folate, choline, betaine, and B vitamins. Hypomethylation contributes to genome instability. Hypermethylation causes the inactivation of tumor suppressor genes. Bioactive nutrients can protect the body at the molecular level ensuring the availability of components necessary for chemical processes at the cellular level. Polyphenols, Vitamin B, choline, and methionine affect DNA methylation reducing the risk for lung cancer.
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