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      Epigenetic mechanisms as a new approach in cancer treatment: An updated review


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          Epigenetic, along with genetic mechanisms, is essential for natural evolution and maintenance of specific patterns of gene expression in mammalians. Global epigenetic variation is inherited somatically and unlike genetic variation, it is dynamic and reversible. They are somatically associated with known genetic variations.

          Recent studies indicate the broad role of epigenetic mechanisms in the initiation and development of cancers, that they are including DNA methylation, histone modifications, nucleosomes changes, non-coding RNAs. The reversible nature of epigenetic changes has led to the emergence of novel epigenetic therapeutic approaches, so that several types of these medications have been approved by the FDA so far.

          In this review, we discuss the concept of epigenetic changes in diseases, especially cancers, the role of these changes in the onset and progression of cancers and the potential of using this knowledge in designing novel therapeutic strategies.

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          Most cited references51

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          Hypomethylation distinguishes genes of some human cancers from their normal counterparts.

          It has been suggested that cancer represents an alteration in DNA, heritable by progeny cells, that leads to abnormally regulated expression of normal cellular genes; DNA alterations such as mutations, rearrangements and changes in methylation have been proposed to have such a role. Because of increasing evidence that DNA methylation is important in gene expression (for review see refs 7, 9-11), several investigators have studied DNA methylation in animal tumours, transformed cells and leukaemia cells in culture. The results of these studies have varied; depending on the techniques and systems used, an increase, decrease, or no change in the degree of methylation has been reported. To our knowledge, however, primary human tumour tissues have not been used in such studies. We have now examined DNA methylation in human cancer with three considerations in mind: (1) the methylation pattern of specific genes, rather than total levels of methylation, was determined; (2) human cancers and adjacent analogous normal tissues, unconditioned by culture media, were analysed; and (3) the cancers were taken from patients who had received neither radiation nor chemotherapy. In four of five patients studied, representing two histological types of cancer, substantial hypomethylation was found in genes of cancer cells compared with their normal counterparts. This hypomethylation was progressive in a metastasis from one of the patients.
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            Chromosomal instability and tumors promoted by DNA hypomethylation.

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              Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer.

              Densely methylated DNA associates with transcriptionally repressive chromatin characterized by the presence of underacetylated histones. Recently, these two epigenetic processes have been dynamically linked. The methyl-CpG-binding protein MeCP2 appears to reside in a complex with histone deacetylase activity. MeCP2 can mediate formation of transcriptionally repressive chromatin on methylated promoter templates in vitro, and this process can be reversed by trichostatin A (TSA), a specific inhibitor of histone deacetylase. Little is known, however, about the relative roles of methylation and histone deacetylase activity in the stable inhibition of transcription on densely methylated endogenous promoters, such as those for silenced alleles of imprinted genes, genes on the female inactive X chromosome and tumour-suppressor genes inactivated in cancer cells. We show here that the hypermethylated genes MLH1, TIMP3 (TIMP3), CDKN2B (INK4B, p15) and CDKN2A (INK4, p16) cannot be transcriptionally reactivated with TSA alone in tumour cells in which we have shown that TSA alone can upregulate the expression of non-methylated genes. Following minimal demethylation and slight gene reactivation in the presence of low dose 5-aza-2'deoxycytidine (5Aza-dC), however, TSA treatment results in robust re-expression of each gene. TSA does not contribute to demethylation of the genes, and none of the treatments alter the chromatin structure associated with the hypermethylated promoters. Thus, although DNA methylation and histone deacetylation appear to act as synergistic layers for the silencing of genes in cancer, dense CpG island methylation is dominant for the stable maintenance of a silent state at these loci.

                Author and article information

                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                18 June 2018
                December 2018
                18 June 2018
                : 5
                : 4
                : 304-311
                [a ]Immunology Research Center, Tabriz University of Medical Science, Tabriz, Iran
                [b ]Molecular Medicine Research Center, Tabriz University of Medical Science, Tabriz, Iran
                [c ]Hematology and Oncology Research Center, Tabriz University of Medical Science, Tabriz, Iran
                [d ]Department of Immunology, Division of Hematology and Blood Transfusion Medicine, Tabriz University of Medical Science, Tabriz, Iran
                [e ]Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
                Author notes
                []Corresponding author. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. m.farshdousti@ 123456gmail.com
                © 2018 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 11 May 2018
                : 12 June 2018

                cancer, epigenetic, mechanisms, treatment, methylation


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