Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Taxol is a first-line chemoagent used for treatment of nasopharyngeal carcinoma (NPC). A major obstacle to achieving successful treatment is the development of cellular taxol drug resistance. Aberrant DNA methylation has been recognized to be associated with the transcriptional inactivation of genes related to cancer drug resistance development. To identify the mechanism of DNA methylation involved in NPC taxol resistance, we applied a genome-wide DNA methylation microarray assay to reveal methylation alteration in taxol-resistant NPC cell lines (CNE-1/taxol, 5-8F/taxol, HNE-2/taxol) established previously in our laboratory. Combining with gene expression microarray, we identified drug resistance-associated genes in taxol-resistant cell lines. We also investigated the coeffect of taxol and the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) to confirm the involvement of DNA methylation. The methylation profiling revealed differential patterns between the drug-sensitive and -resistant cell lines. As a result, taxol-resistant cell lines were detected to be globally hypermethylated. Forty-eight differentially methylated genes (30 hypermethylated and 18 hypomethylated) were further identified commonly in the three taxol-resistant cell lines. Six of them (DLC1, CHFR, ABCC5, PEG10, ERBB2, and GSTP1) were independently confirmed to contribute to taxol resistance by both methylation-specific PCR and quantitative real-time PCR. Finally, we conclude that DNA methylation is closely correlated with taxol drug resistance in NPC cells. Combined analysis of DNA methylation and gene expression may enable the discovery of new therapeutic targets and prognostic biomarkers of cancers. Furthermore, DNA methylation inhibitors can reverse chemoresistance and prevent the development of acquired drug resistance.
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PMID:Genomic methylation profiling combined with gene expression microarray reveals the aberrant methylation mechanism involved in nasopharyngeal carcinoma taxol resistance. 2282 24

Ionizing radiation can induce deoxyribonucleic acid (DNA) methylation pattern change, and ionizing radiation-induced oxidative damage may also affect DNA methylation status. However, the influence of low-dose ionizing radiation, such as occupational radiation exposure, on DNA methylation is still controversial.By investigating the relationship between occupational radiation exposure and DNA methylation changes, we evaluated whether radiation-induced oxidative damage was related to DNA methylation alterations and then determined the relationship among occupational radiation level, DNA methylation status, and oxidative damage in interventional physicians.The study population included 117 interventional physicians and 117 controls. We measured global methylation levels of peripheral blood leukocyte DNA and expression level of DNA methyltransferase (Dnmts) and homocysteine (Hcy) in serum to assess the DNA methylation status of the body. We measured 8-hydroxy-2'-deoxyguanosine (8-OHDG) and 4-hydroxynonenal (4-HNE) levels as indices of oxidative damage. Relevance analysis between multiple indices can reflect the relationship among occupational radiation exposure, DNA methylation changes, and oxidative damage in interventional physicians.The expression levels of Dnmts, 4-HNE, and 8-OHDG in interventional physicians were higher than those in controls, while there was no statistical difference in total DNA methylation rate and expression of Hcy between interventional physicians and controls. Total cumulative personal dose equivalent in interventional physicians was positively correlated with the expression levels of Dnmts, 8-OHDG, and 4-HNE. The expression levels of 8-OHDG in interventional physicians were negatively correlated with global DNA methylation levels and positively correlated with the expression levels of Hcy.Occupational radiation exposure of interventional physicians has a certain effect on the expression of related enzymes in the process of DNA methylation, while ionizing radiation-induced oxidative damage also has a certain effect on DNA methylation. However, there was no evidence that dose burden of occupational exposure was associated to changes of DNA methylation status of interventional physicians, since it is rather unclear which differences are observed among the effects produced by radiation exposure and oxidative damage.
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PMID:The relationship among occupational irradiation, DNA methylation status, and oxidative damage in interventional physicians. 3157 86

This study is intended to investigate the epigenetic regulation of the most conserved molecular chaperone, HSP70 and its potential role in the pathophysiology of pseudoexfoliation syndrome (PEXS) and glaucoma (PEXG), a protein aggregopathy, contributing significantly to world blindness. Expression levels of HSP70 were significantly decreased in the lens capsule (LC) of PEXS but not in PEXG compared with that in control. Bisulfite sequencing of the LC of the study subjects revealed that the CpG islands (CGIs) located in the exonic region but not in the promoter region of HSP70 displayed hypermethylation only in PEXS individuals. There was a corresponding increase in DNA methyltransferase 3A (DNMT3A) expression in only PEXS individuals suggesting de novo methylation in this stage of the disease condition. On the other hand, peripheral blood of both PEXS and PEXG cases showed hypermethylation in the exonic region when compared with non-PEX controls displaying tissue-specific effects. Further, functional analyses of CGI spanning the exon revealed a decreased gene expression in the presence of methylated in comparison with unmethylated reporter gene vectors. Treatment of human lens epithelial B-3 (HLE B-3) cells with DNMT inhibitor restored the expression of HSP70 following depletion in methylation level at exonic CpG sites. In conclusion, a decreased HSP70 expression correlates with hypermethylation of a CGI of HSP70 in PEXS individuals. The present findings enhance our current understanding of the mechanism underlying HSP70 repression, contributing to the pathogenesis of PEX.
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PMID:Epigenetic silencing of heat shock protein 70 through DNA hypermethylation in pseudoexfoliation syndrome and glaucoma. 3212 24