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      Methyl Donor Micronutrients that Modify DNA Methylation and Cancer Outcome

      review-article
      1 , 2 , * , 1 , 2
      Nutrients
      MDPI
      methyl donors, nutrients, DNA methylation, cancer, folate, Vitamin B, choline, betaine, methyltransferase, dietary

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          Abstract

          DNA methylation is an epigenetic mechanism that is essential for regulating gene transcription. However, aberrant DNA methylation, which is a nearly universal finding in cancer, can result in disturbed gene expression. DNA methylation is modified by environmental factors such as diet that may modify cancer risk and tumor behavior. Abnormal DNA methylation has been observed in several cancers such as colon, stomach, cervical, prostate, and breast cancers. These alterations in DNA methylation may play a critical role in cancer development and progression. Dietary nutrient intake and bioactive food components are essential environmental factors that may influence DNA methylation either by directly inhibiting enzymes that catalyze DNA methylation or by changing the availability of substrates required for those enzymatic reactions such as the availability and utilization of methyl groups. In this review, we focused on nutrients that act as methyl donors or methylation co-factors and presented intriguing evidence for the role of these bioactive food components in altering DNA methylation patterns in cancer. Such a role is likely to have a mechanistic impact on the process of carcinogenesis and offer possible therapeutic potentials.

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          TET enzymes, TDG and the dynamics of DNA demethylation.

          DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.
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            DNA Methylation in Cancer and Aging.

            DNA methylation is known to be abnormal in all forms of cancer, but it is not really understood how this occurs and what is its role in tumorigenesis. In this review, we take a wide view of this problem by analyzing the strategies involved in setting up normal DNA methylation patterns and understanding how this stable epigenetic mark works to prevent gene activation during development. Aberrant DNA methylation in cancer can be generated either prior to or following cell transformation through mutations. Increasing evidence suggests, however, that most methylation changes are generated in a programmed manner and occur in a subpopulation of tissue cells during normal aging, probably predisposing them for tumorigenesis. It is likely that this methylation contributes to the tumor state by inhibiting the plasticity of cell differentiation processes. Cancer Res; 76(12); 3446-50. ©2016 AACR.
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              DNMT1 and DNMT3b cooperate to silence genes in human cancer cells.

              Inactivation of tumour suppressor genes is central to the development of all common forms of human cancer. This inactivation often results from epigenetic silencing associated with hypermethylation rather than intragenic mutations. In human cells, the mechanisms underlying locus-specific or global methylation patterns remain unclear. The prototypic DNA methyltransferase, Dnmt1, accounts for most methylation in mouse cells, but human cancer cells lacking DNMT1 retain significant genomic methylation and associated gene silencing. We disrupted the human DNMT3b gene in a colorectal cancer cell line. This deletion reduced global DNA methylation by less than 3%. Surprisingly, however, genetic disruption of both DNMT1 and DNMT3b nearly eliminated methyltransferase activity, and reduced genomic DNA methylation by greater than 95%. These marked changes resulted in demethylation of repeated sequences, loss of insulin-like growth factor II (IGF2) imprinting, abrogation of silencing of the tumour suppressor gene p16INK4a, and growth suppression. Here we demonstrate that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and provide compelling evidence that such methylation is essential for optimal neoplastic proliferation.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                13 March 2019
                March 2019
                : 11
                : 3
                : 608
                Affiliations
                [1 ]Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, 1919 W. Taylor St. (AHSB), Room 433, Chicago, IL 60612, USA; mali37@ 123456uic.edu
                [2 ]Integrative Physiology Laboratory, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
                Author notes
                [* ]Correspondence: amahmo4@ 123456uic.edu ; Tel.: +1-312-753-9998
                Article
                nutrients-11-00608
                10.3390/nu11030608
                6471069
                30871166
                880168c2-b53f-446c-ade7-e52a6957fbcb
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 February 2019
                : 07 March 2019
                Categories
                Review

                Nutrition & Dietetics
                methyl donors,nutrients,dna methylation,cancer,folate,vitamin b,choline,betaine,methyltransferase,dietary

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