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

DNA methylation is essential in X chromosome inactivation and genomic imprinting, maintaining repression of XIST in the active X chromosome and monoallelic repression of imprinted genes. Disruption of the DNA methyltransferase genes DNMT1 and DNMT3B in the HCT116 cell line (DKO cells) leads to global DNA hypomethylation and biallelic expression of the imprinted gene IGF2 but does not lead to reactivation of XIST expression, suggesting that XIST repression is due to a more stable epigenetic mark than imprinting. To test this hypothesis, we induced acute hypomethylation in HCT116 cells by 5-aza-2'-deoxycytidine (5-aza-CdR) treatment (HCT116-5-aza-CdR) and compared that to DKO cells, evaluating DNA methylation by microarray and monitoring the expression of XIST and imprinted genes IGF2, H19, and PEG10. Whereas imprinted genes showed biallelic expression in HCT116-5-aza-CdR and DKO cells, the XIST locus was hypomethylated and weakly expressed only under acute hypomethylation conditions, indicating the importance of XIST repression in the active X to cell survival. Given that DNMT3A is the only active DNMT in DKO cells, it may be responsible for ensuring the repression of XIST in those cells. Taken together, our data suggest that XIST repression is more tightly controlled than genomic imprinting and, at least in part, is due to DNMT3A.
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PMID:Stability of XIST repression in relation to genomic imprinting following global genome demethylation in a human cell line. 2538 68