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    • Neuropeptide Y 13-36 (porcine) kinase The aberrant methylati

    2019-10-15

    The aberrant methylation of genes that suppress tumorigenesis appears to occur early in tumor development and increase progressively, eventually leading to the malignant phenotype [35]. Genes involved in every step of tumorigenesis can be silenced by this epigenetic mechanism. Hypermethylation of promoter regions, which is associated with transcriptional silencing, is at least as common as DNA mutation as a mechanism for inactivation of classical tumor suppressor genes in human cancers [36]. A correlation has been shown between the methylation of the DAPK-1 promoter and subsequent lack of DAPK-1 protein expression in superficial tumors of urothelial carcinomas [37]. Furthermore, hypermethylation of DAPK has been found to be a useful prognostic marker for disease recurrence in superficial Neuropeptide Y 13-36 (porcine) kinase cancers [37]. Catto et al. has demonstrated that the DAPK promoter methylation was present in 86% of urothelial carcinoma. In a previous study, we also found the DAPK gene was hypermethylated and the expression of DAPK protein was decreased by arsenite using methylation-specific PCR (MSP) [18]. Although inorganic arsenic is clearly a carcinogenic agent for humans, it is unclear if this is through genotoxic or epigenetic pathways. The epigenetic mechanism could be via regulated activation or inactivation of signal transduction pathways resulting in aberrant cell accumulation. Recent evidence suggests that abnormal T cell ERK pathway signal transduction may be fundamental to some of these abnormalities through effects on DNA methylation [38]. They have suggested that DNA methyltransferase (DNMT) is decreased by inhibiting signaling through the ras-MAPK pathway in human T cells [39]. The methylation of mammalian genomic DNA is catalyzed by DNMT, which play a special role in the initiation of chromatin remolding and gene expression regulation. The DNMT use S-adenosly-l-methionine (AdoMet) as a donor for methyl groups [40]. In addition, the T cells of lupus patients show decreased DNMT mRNA and enzyme activity, resulting in DNA hypomethylation [41]. Although activation of the MAPK/ERK pathway is involved in pathogenesis, progression, and oncogenic behavior of human bladder cancer [42], little is known about mechanisms that inhibit MAPK use to induce the expression of tumor suppressor genes, and no data are yet available on the relationship among MAPK/ERK, DNMT1, and DNA methylation in human cancer cells, including bladder cancer. In one study, they found that the ERK signaling pathway was involved in the activation of DNMT3b transcription by RAS [43]. In addition, some studies have shown that ERK might directly phosphorylate Sp1 and activate Sp1-controlled gene transcription [44]. Recently, they found that hindering MAPK/ERK activity by inhibiting or blocking MEK1/2 via RNAi transfection down-regulated DNMT1 mRNA and protein expression levels in a similar fashion as did the DNMT inhibitor in SW1116 cells. The MAPK/ERK inhibitors, particularly rottlerin, resulted in the demethylation of p16 and p21. Cell differentiation requires the proper balance of activation and inhibition of the MAPK/ERK signal transduction pathway, and inhibitors affecting cell cycle regulation in the SW1116 cell line are consistent with the view that MAPK/ERK signaling may regulate DNA methylation [45]. Taken together, these experiments provide direct evidence linking endogenous ERK activation to DNA methylation in cancer cell lines. It indicates the ERK pathway plays a key role of regulated DNA methylation in cells. Previously, we found arsenite-induced DAPK promoter hypermethylation [18], [46]. In this study, we found the expression of DAPK proteins was decreased by arsenite using ICC and Western blotting. However, cell pretreatment with inhibitors (5-aza-CdR or U0126) suppressed the effect of arsenite on DAPK protein expression. The evidence suggested that arsenite-induced DAPK hypermethylation and decreased protein levels via ERK activation in SV-HUC-1 cells. It has been shown that DAPK promotes the cytoplasmic retention of ERK, thereby inhibiting ERK signaling in the nucleus. In addition, when DAPK-1 mutation alters the oligomeric structure of the death domain, de-stabilizes DAPK-1 binding to ERK, and prevents ERK:DAPK-1-dependent apoptosis [47]. However, the arsenite-induced DAPK hypermethylation, it will lose this inhibiting ability of ERK. The reciprocal regulation between ERK and DAPK plays a positive and physiological role in apoptosis [48]. When SV-HUC-1 cells pretreatment with 5-aza-CdR or U0126 can restore the DAPK expression and induce apoptosis by DAPK. The 5-aza-CdR is a pyrimidine nucleoside analog that strongly inhibits DNA methyltransferase activity and as such is one of the strongest inhibitors of DNA methylation [49]. The incorporation of 5-aza-CdR into DNA can block DNA methylation [50], which can result in gene activation and the induction of differentiation [42]. The potential to increase the 5-aza-CdR chemosensitivity of cancer cell lines and induce apoptosis has been proven in vitro[51], [52]. Taken together, these results suggest the effect of arsenite on DAPK via ERK activation and induced apoptosis by DAPK in SV-HUC-1 cells.