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  • PF 4800567 hydrochloride synthesis DNA hypomethylation has b


    DNA hypomethylation has been found in liver tumor and other tumors of humans, such as laryngeal cancer, PF 4800567 hydrochloride synthesis tumors, tongue squamous cell carcinoma and uterine leiomyomas [[20], [21], [22], [23], [24]]. Then, we mainly sought to confirm whether TCA could induce DNA hypomethylation in vitro and the possible link between hypomethylation and DNA methyltransferase expression levels. DNA methyltransferase expression was decreased in TCA treated cells while increased in HepG2 cells, which might be associated with the cell proliferation levels [25]. Furthermore, we found that 5-aza-dC treated cells showed the same fluctuated tendency of DNA methyltransferases in TCA treated cells, but these two drugs induced DNA hypomethylation probably with the different mode. The former substitutes the cytosine while the latter intends to interfere the cytosine metabolic [26]. After withdrawal of TCA, the recovery cells showed an increase in DNA methyltransferase expression level (still lower than normal), so it seems that TCA is one of the DNA methyltransferase inhibitors. Decreased DNA methyltransferase activity has been found in liver of mice exposed to TCA while increased activity in TCA induced liver tumors [27]. Our research might provided the reason in time. In theory, we could easily deduce that the down-regulated DNMT1 and DNMT3a caused the global hypomethylation in TCA treated cells, while DNMT3b had little effect during the process. The hypomethylation status might be achieved in two ways: the decreased DNMT1 expression and DNMT3a expression. DNA methyltransferase expression levels are crucial components of cellular machinery maintaining and establishing DNA methylation patterns. The former action is due to DNMT1, while the latter is in charge of DNMT3a and DNMT3b. So these two mechanism both taken part in the process of DNA demethylation in TCA treated cells. The major DNA methyltransferase activity in somatic cells is provided by DNMT1, which is an essential genomic regulator for murine liver histogenesis and regeneration [28]. Thus, the decreased DNMT1 may play more important role in TCA induced hypomethylation process. Two possible mechanism of carcinogenesis associated with TCA induced hypomethylation: the decreased DNA methylation can be one of precancerous lesions to cancer; on the other hand, the hypomethylation status of DNA can up-regulate many oncogene. Therefore, hypomethylation can be used as a biomarker for TCA-related diseases. The TCA treated cells with decreased DNMT1 and DNMT3a expression levels would be likely to tolerate the DNA hypomethylation status because its total methylation capability became weak. The decreased DNA methylation would make the DNA predispose to genetic alterations which often lead to malignant transformation.
    Conflicts of interest
    Acknowledgments National Natural Science Foundation of China (81473014); Top Young Talents of Guangdong Hundreds of Millions of Projects (87316004); Jinan University High-level University Construction Public Health and Preventive Medicine Fund (JNUPHPM2016003)
    Introduction In mammals and plants, DNA methylation is associated with silenced regions of the genome known as heterochromatin. In mammals, disrupted DNA methylation is associated with various developmental defects and cancers (Kulis and Esteller, 2010, Messerschmidt et al., 2014, Robertson, 2005). In plants, aberrant DNA methylation patterns can lead to severe developmental phenotypes (Jacobsen and Meyerowitz, 1997, Lindroth et al., 2001). For DNA methylation to be effective, it must be maintained across multiple generations (Edwards et al., 2017, Law and Jacobsen, 2010, Torres and Fujimori, 2015, Zhang et al., 2018a). The biochemical and structural basis for how such DNA methylation is faithfully reproduced within the appropriate chromatin context is poorly understood. In mammals, three DNA methyltransferase (MTase) enzymes, DNMT1, DNMT3A, and DNMT3B, promote silencing of repetitive and transposable elements and methylate CG sites in the promoters of inactive genes (Smith and Meissner, 2013). DNMT1 is thought to maintain DNA methylation during DNA replication, whereas DNMT3A and DNMT3B are primarily de novo methyltransferase enzymes. In Arabidopsis thaliana, four active DNA methyltransferase enzymes have been identified: DRM2, CMT2, CMT3, and MET1 (Du et al., 2015). The focus of this study, ZMET2, is an ortholog of CMT3 from Zea mays (maize) and, like CMT3, is thought to primarily methylate CHG sites (where H = A, T, or C) (Bartee et al., 2001, Du et al., 2012, Lindroth et al., 2001, Papa et al., 2001). Both DNMT1 and CMT3/ZMET2 are classified as maintenance methyltransferases based on their co-localization with replication machinery in vivo and, in the case of DNMT1, preference for hemimethylated DNA in vitro. Although DNMT1 has been shown to have a preference for hemimethylated DNA, the relative activity of ZMET2 on hemimethylated versus unmethylated DNA substrates has not been reported (Du et al., 2012, Jeltsch and Jurkowska, 2016).