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

The mechanisms underlying ectopic methylation of CpG islands in neoplastic cells are poorly understood. One determinant may be the increased expression of DNA methyltransferase (DNA MTase) observed frequently in neoplastic cells. To evaluate the role of DNA MTase overexpression in aberrant CpG island methylation, we assessed methylation of fibroblast-derived CpG islands in human diploid fibroblast x fibrosarcoma hybrid cell lines. Each of six independently derived, immortalized hybrid cell lines exhibited a high level of DNA MTase expression, comparable to that of the fibrosarcoma parental line. The methylation status of five CpG island loci, each of which was methylated extensively in the fibrosarcoma parental cells but not in the fibroblasts, was then determined in the hybrid cell lines. The patterns of methylation were consistent and highly locus dependent among the hybrid lines. Unmethylated alleles were retained stably at three loci. The parental origin of alleles could be determined at two other loci in the hybrid cells. Whereas no methylation of parental fibroblast-derived alleles of the HIC-1 locus was noted in hybrid cell lines, a marked increase in methylation of fibroblast-derived alleles of the estrogen receptor was observed in all hybrid cell lines. Therefore, despite high-level DNA MTase expression, widespread loss of unmethylated CpG islands was not observed in the hybrid cell lines. The nonrandom pattern of increased CpG island methylation in the hybrid cell lines suggests that locus-specific features and/or clonal selection, and not just DNA MTase expression, affect the evolution of ectopic methylation in neoplastic cells. Somatic cell hybrids may provide useful models for studying aberrant epigenetic events in neoplastic cells.
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PMID:Retention of unmethylated CpG island alleles in human diploid fibroblast x fibrosarcoma hybrids expressing high levels of DNA methyltransferase. 878 Aug 98

Aberrant DNA methylation and increased expression of DNA methyltransferases (DNMTs) are features of tumor cells. To investigate roles for DNMTs during hepatocarcinogenesis, we examined DNMT expression at both the mRNA and protein level in hepatocellular carcinomas (HCCs) and paired non-neoplastic liver tissues, along with measuring the DNA methylation status of five tumor suppressor genes. Expression of DNMT1, DNMT3a and DNMT3b mRNA was detected in 33.3, 59.3, and 55.6% of HCCs and 40.7, 22.2, and 0% of non-neoplastic liver tissues, respectively. DNMT1 and DNMT3a were immunoreactive in 100 and 48% of HCCs and 52 and 0% of non-neoplastic liver tissues. The DNMT3a mRNA expression profile showed significant correlation with its immunoreactivity (P=0.022). DNA methylation status of five tumor suppressor genes, HIC-1, p16, RASSF1A, p53, and RB1 was detected in 85.2, 48.1, 44.4, 22.2, and 0% of HCCs, respectively. There was no significant correlation between DNMT mRNA expression and DNA methylation (P>0.05). DNMT immunoreactivity was also not associated with DNA methylation except HIC-1 (P=0.036) and p53 methylation (P=0.009). Despite the lack of correlation between DNA methylation status and DNMT expression, the frequency of hypermethylation of tumor suppressor genes remained relatively high in HCCs, suggesting that regional DNA hypermethylation is involved in hepatocarcinogenesis and that there may be other mechanisms for increasing DNA methylation.
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PMID:DNA methyltransferase expression and DNA hypermethylation in human hepatocellular carcinoma. 1588 82

Aberrant DNA methylation on CpG islands is one of the most consistent epigenetic changes in human cancers, and the methylation process is catalyzed by DNA methyltransferase (DNMT). We evaluated i) the mRNA levels of three DNMTs; DNMT1, DNMT3a and DNMT3b, in 25 hepatocellular carcinomas (HCCs), in their corresponding non-cancerous liver tissues and in 7 normal livers by using real-time reverse transcriptase-polymerase chain reaction; ii) nuclear expression of DNMT1 and DNMT3a proteins in the HCCs by immunohistochemistry, iii) the methylation status of 5 genes; p16, p15, E-cadherin, HIC-1 and RASSF1A in the same tissues, and iv) the relationships between the above results and the clinicopathological characteristics, including prognosis. The differences in mRNA expression levels for DNMT1, DNMT3a and DNMT3b were statistically significant between HCC and normal livers (p<0.001), HCC and chronic hepatitis (p<0.001) and HCC and cirrhosis (p<0.001). An increase in mRNA expression levels of >4-fold for DNMT3b in HCCs was significantly associated with a poorer overall survival (p=0.027) and shorter metastasis-free survival (p=0.0299). A poorer recurrence-free survival was noted in HCCs with a >4-fold increase in DNMT3a mRNA (p=0.0120). The average numbers of methylated genes were 0, 1.27, 1.38 and 2.72 for normal livers, chronic hepatitis, cirrhosis and HCCs, respectively, and this progressive increase from normal livers to chronic hepatitis/cirrhosis through HCC may suggest that tumor suppressor gene methylation is an early event in hepatocarcinogenesis. These results first suggest that hepatocarcinogenesis involves an increased expression of DNMT1, DNMT3a and DNMT3b mRNA and a progressive increase in the number of methylated genes from normal liver, chronic hepatitis/cirrhosis to HCC and secondly that an increase in the DNMT3a and DNMT3b mRNA levels in HCCs relative to their non-cancerous tissues may be a predictor of poor survival.
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PMID:DNA methyltransferase expression and DNA methylation in human hepatocellular carcinoma and their clinicopathological correlation. 1754 90