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Genes and heredity in breast cancer
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
Methylation and demethylation of DNA is a common tool for regulating DNA transcription. When the process of DNA methylation is altered, genes involved in carcinogenesis can be structurally normal but transcribed wrongly, giving origin to a cancer or contributing to its development. This mechanism is called ‘epigenetic’, in that genes are not directly involved.
Role of Ascorbate and Dehydroascorbic Acid in Metabolic Integration of the Cell
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Gábor Bánhegyi, András Szarka, József Mandl
ε-N-trimethyl-l-lysine hydroxylase and β-butyrobetaine hydroxylase, enzymes necessary for synthesis of carnitine, seem to be localized to the mitochondria and cytosol. Carnitine is essential for the transport of fatty acids into mitochondria for β-oxidation and consequent ATP generation [66]. However, the subcellular localization of 4-hydroxyphenylpyruvate dioxygenase, the enzyme that participates in the catabolism of tyrosine, is less known. In the nucleoplasm Fe(II)/2-oxoglutarate–dependent dioxygenases are involved in the epigenetic regulation of gene expression by demethylating histones and DNA [55]. Enzymes that demethylate histones mainly belong to the Jumonji protein family conserved from yeast to humans with a common jmjC functional domain [82]. DNA demethylation occurs at the methyl group of 5-methylcytosine via subsequent oxidative steps catalyzed by the dioxygenases of the ten-eleven translocation (TET) family [35,45].
Methylome and epigenetic markers
Published in Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos, New Technologies and Perinatal Medicine, 2019
Skevi Kyriakou, Marios Ioannides, George Koumbaris, Philippos Patsalis
DNA methylation is mediated by DNA methyl transferases (DNMT), which are enzymes responsible for catalyzing, recognizing, adding, and removing methyl groups. They are separated into two main classes: writers and erasers. Writers catalyze the addition of the methyl group onto cytosine residues, and erasers are associated with methyl group modification and removal. Specifically, DNMT1 is responsible for maintaining the heritable methyl group on the cytosine residues and has a preference for hemimethylated CpG sites generated by DNA replication (5). DNMT3A and DNMT3B are de novo methyltransferases responsible for methylating CpGs missed by DNMT1 (6,7). When DNA demethylation is required, either a passive or an active demethylation process takes place. Passive demethylation involves the inhibition of DNMT1 during cell replication in dividing cells. Active DNA demethylation involves enzymatic reactions to remove the methyl group from the cytosine residues, and it occurs in both dividing and nondividing cells (8). This mechanism allows for the embryonic development by controlling expression of genes at specific times and tissues.
Potential of IDH mutations as immunotherapeutic targets in gliomas: a review and meta-analysis
Published in Expert Opinion on Therapeutic Targets, 2021
Nazareno Gonzalez, Antonela S. Asad, José Gómez Escalante, Jorge A. Peña Agudelo, Alejandro J. Nicola Candia, Matías García Fallit, Adriana Seilicovich, Marianela Candolfi
Epigenetic therapies, such as 5-azacytidine and decitabine (DAC), bind irreversibly to DNA methyltransferases (DNMTs) and inhibit DNA methylation processes. These DNA-demethylating agents have shown promising results in acute myeloid leukemia (AML) [67–69]. However, trying to use these agents in solid and heterogeneous tumors like gliomas is a matter of debate. In preclinical studies, 5-azacytidine was shown not only to reduce the methylation phenotype, but also to induce tumor regression in a patient-derived mIDH1 glioma xenograft [70]. On the other hand, DAC showed promising antitumor effects in mIDH1 glioma cells, by promoting cell differentiation and growth inhibition [71]. Recently, treatment of tumors with 5-azacytidine selectively increased survival of mice bearing mIDH1 glioma tumors, but not wtIDH1 ones, showing once again that mIDH1 tumors are sensitive to DNA demethylating treatments [70]. Moreover, 5-Azacytidine in combination with TMZ increased DNA damage response in mIDH1 glioma, inducing cell growth inhibition and apoptosis in subcutaneous and orthotopic patient-derived xenografts mIDH1 models of glioma [72]. Lastly, several clinical trials are evaluating the therapeutic effects of 5-azacytidine as single agent (NCT03666559) or in combination with the mIDH1 inhibitor FT-2102, in patients with recurrent gliomas with mIDH (NCT03684811). These results indicate that mIDH tumors largely depend on their distinct epigenome. Thus, trying to develop different combination approaches using demethylating agents may represent a successful therapeutic alternative.
Characterization of DNA hydroxymethylation profile in cervical cancer
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Jing Wang, Yi Su, Yongju Tian, Yan Ding, Xiuli Wang
DNA methylation as a well-studied epigenetic hallmark has been determined to play a crucial role in cancers and other human diseases. In general, the presence of aberrant DNA hypermethylation is observed to cause the abnormal chromosome activity and gene silencing in most of the cancers [22]. As we know, DNA methyltransferases (DNMTs) contribute to the hypermethylation via the transfer of the methyl groups on the cytosines. Thus, DNMT inhibitors such as decitabine or azacytidine have been applied or combined with other drugs for the treatment of solid cancers [23]. Nevertheless, the persistently accumulated hypermethylation status of cancers also implies the other side that the process of DNA demethylation is blocking. For DNA demethylation, passive demethylation reduces the global 5mC level via suppression of DNA methylation information inheritance in daughter cells, while the active demethylation happens in situ to restore the 5mC to regular cytosine. It is widely acknowledged that 5mC is oxidized to 5hmC, 5foC and 5caC step by step and finally is decarboxylated to regular cytosine by thymine-DNA glycosylase (TDG). Here, we determine that the global 5mC is up-regulated while 5hmC was down-regulated (Figure 1), and 5hmC is negatively correlated with the malignancy of cervical cancer, which indicates that the active DNA demethylation is restrained in cervical cancer. We speculate that the active demethylation process is terminated and hydroxymethylation is blocked so that the overall hypermethylated DNA is abnormally accumulated in cervical cancer.
The role of pharmacogenomics in adverse drug reactions
Published in Expert Review of Clinical Pharmacology, 2019
Ramón Cacabelos, Natalia Cacabelos, Juan C. Carril
DNA demethylation can be produced by at least 3 enzyme families: (i) the ten-eleven translocation (TET) family, mediating the conversion of 5mC into 5hmC; (ii) the AID/APOBEC family, acting as mediators of 5mC or 5hmC deamination; and (iii) the BER (base excision repair) glycosylase family involved in DNA repair [27]. The DNA demethylation pathway plays a significant role in DNA epigenetics. This pathway removes the methyl group from cytosine, which is involved in the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) by ten-eleven translocation (TET) proteins. Then, 5-hmC can be iteratively oxidized to generate 5-formylcytosine and 5-carboxylcytosine [61]. The oxidation of 5-methylcytosine can result in three chemically distinct species: 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxycytosine [62].