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)

To cast light on the contribution of methylation to genesis of ulcerative colitis (UC)-associated tumors, promoter methylation and expression of O6-methylguanine DNA methyltransferase (MGMT), hMLH1, p16INK4, and E-cadherin were examined in 14 low-grade dysplasias (LGDs), 15 high-grade dysplasias (HGDs), and 14 adenocarcinomas associated with UC and, for comparison, in 30 sporadic adenomas with LGD, 30 adenomas with HGD, and 60 adenocarcinomas, using methylation-specific polymerase chain reaction and immunohistochemical analysis. The frequency of MGMT and hMLH1 methylation in UC-associated tumors was low, with a significant difference between HGD and sporadic adenomas with HGD of the left hemicolon. The methylation frequency of p16INK4 in UC-associated tumors was also relatively low compared with sporadic colonic tumors. For E-cadherin, methylation was limited in both types of tumor. Decrease of expression of MGMT, hMLH1, and p16INK4 was significantly correlated with methylation. Thus, compared with the sporadic type, contribution of methylation to UC-associated tumorigenesis seems to be low.
 ...
PMID:Low frequency of promoter methylation of O6-methylguanine DNA methyltransferase and hMLH1 in ulcerative colitis-associated tumors: comparison with sporadic colonic tumors. 1727 33

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.
 ...
PMID:DNA methyltransferase expression and DNA methylation in human hepatocellular carcinoma and their clinicopathological correlation. 1754 90

The onset and progression of cancer is associated with the methylation-dependent silencing of specific genes, however, the mechanism and its regulation have not been established. We previously demonstrated that reduction of mitochondrial DNA content induces cancer progression. Here we found that mitochondrial DNA-deficient LNrho0-8 activates the hypermethylation of the nuclear DNA promoters including the promoter CpG islands of the endothelin B receptor, O6-methylguanine-DNA methyltransferase, and E-cadherin. These are unmethylated and the corresponding gene products are expressed in the parental LNCaP containing mitochondrial DNA. The absence of mitochondrial DNA induced DNA methyltransferase 1 expression which was responsible for the methylation patterns observed. Inhibition of DNA methyltransferase eliminated hypermethylation and expressed gene products in LNrho0-8. These studies demonstrate loss or reduction of mitochondrial DNA resulted in the induction of DNA methyltransferase 1, hypermethylation of the promoters of endothelin B receptor, O6-methylguanine-DNA methyltransferase, and E-cadherin, and reduction of the corresponding gene products.
 ...
PMID:Mitochondrial regulation of cancer associated nuclear DNA methylation. 1796 37

E-cadherin is a major cell adhesion molecule implicated as a potent tumor suppressor, which is frequently altered in human tumors including hepatocellular carcinoma. Here, we report that hepatitis C virus Core downregulates E-cadherin expression at the transcription level. This effect was abolished after treatment of 5'-Aza-2'dC, a specific inhibitor of DNA methyltransferase (DNMT). In addition, this repression was strongly correlated with hypermethylation of CpG islands of E-cadherin promoter via concerted action of both DNMT1 and 3b in Core-expressing cells. The decreased E-cadherin expression results in dramatic morphological changes in Core-expressing cells. In addition, Core-expressing cells aggregate poorly in suspension culture, reflecting their altered cell-cell interactions. The biological significance was further demonstrated by the increased collagen invasion ability of Core-expressing cells. Therefore, our finding suggests that Core plays a role in hepatocellular carcinogenesis by favoring cell detachment from the surrounding cells and migration outside of the primary tumor site.
 ...
PMID:Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. 1816 8

Key to the success of human reproduction is the capacity of an embryo to attach and implant into the endometrial wall after which a nutrient supply is established through placentation. Herein, we have examined the potential epigenetic regulation of uterine receptivity by use of the receptive RL95-2 and nonreceptive AN3-CA endometrial epithelial carcinoma cell lines. Using an in vitro model of embryo implantation, we demonstrate that inhibition of DNA methylation by 5'-aza-2'-deoxycytidine (AZA), resulted in the nonreceptive AN3-CA cell line becoming receptive to BeWo cell spheroid attachment. Examination of components of the adherens junction complex revealed that AZA specifically increased the expression of E-cadherin and plakoglobin at the mRNA and protein levels in AN3-CA cells, and E-cadherin protein expression was found to localize to sites of intercellular contact. Forced expression of E-cadherin in AN3-CA cells significantly enhanced receptivity. Small interfering RNA (siRNA)-mediated depletion of the individual DNA methyltransferase (DNMT) molecules did not induce E-cadherin expression in AN3-CA cells; however, concomitant siRNA-mediated depletion of both DNMT3A and DNMT3B induced the expression of E-cadherin. Furthermore, E-cadherin expression was significantly increased after the concomitant siRNA-mediated depletion of DNMT-1, -3A, and -3B in AN3-CA cells. Therefore, we have provided evidence that E-cadherin plays an important role in uterine receptivity and that E-cadherin expression is epigenetically regulated in AN3-CA cells, suppressed by the combined actions of DNMT-1, -3A, and -3B.
 ...
PMID:Epigenetic regulation of E-cadherin controls endometrial receptivity. 1897 68

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries. In CLL, a large number of genes affecting cancer-related pathways may be dysregulated by epigenetic silencing. We analysed by methylation-specific polymerase chain reaction the CpG island methylation status of 15 well-characterised cancer-related genes in 32 patients with CLL. Aberrant methylation in the sample of patients with CLL was shown for secreted frizzled-related protein 1 (68.8%), secreted frizzled-related protein 2 (65.6%), death-associated protein kinase 1 (50.0%), E-cadherin (21.9%), secreted frizzled-related protein 4 (15.6%), p15 (9.4%), p16 (6.3%), retinoic acid receptor beta2 (3.1%), secreted frizzled-related protein 5 (3.1%) and tissue inhibitor of matrix metalloproteinases 3 (3.1%). For human Mut-L homolog 1, O(6)-methylguanine DNA methyltransferase, p73, suppressor of cytokine signalling 1 and tissue inhibitor of matrix metalloproteinases 2 no hypermethylation was detected. Hypermethylation of at least one gene was observed in 87.5% of the samples. Our results show that aberrant CpG island methylation affecting cancer-related pathways such as Wnt signalling, regulation of apoptosis, cell cycle control and tissue invasion is a common phenomenon in CLL. Epigenetic disturbances may be involved in the pathogenesis of CLL and thus may provide a molecular rationale for therapeutic approaches.
 ...
PMID:CpG island methylation patterns in chronic lymphocytic leukemia. 1934 29

Reexpression of hypermethylated tumor suppressor genes using DNA methyltransferase (DNMT) and histone deacetylase inhibitors occurs by a mechanism whereby promoter demethylation is the dominant event. In support of this model, we found in acute myeloid leukemia cells with hypermethylated p15INK4B and E-cadherin promoters that the DNMT inhibitor, 5-aza-2'-deoxycytidine, induced p15INK4B and E-cadherin expression, and decreased levels of DNA methylation, histone H3 lysine 9 (H3K9) methylation and SUV39H1 associated with p15INK4B and E-cadherin promoters. On the basis of these observations, we examined whether promoter demethylation was dominant to H3K9 demethylation in p15INK4B and E-cadherin reexpression. We observed that SUV39H1 short hairpin RNA and chaetocin, a SUV39H1 inhibitor, induced p15INK4B and E-cadherin expression and H3K9 demethylation without promoter demethylation. Reexpression of hypermethylated p15INK4B and E-cadherin required histone H3K9 demethylation that was achieved directly by inhibiting SUV39H1 expression or activity, or indirectly by decreasing the amount of SUV39H1 associated with the p15INK4B and E-cadherin promoters using 5-aza-2'-deoxycytidine. The results from this study highlight the potential of H3K9 methyltransferases as therapeutic targets for reactivating expression of hypermethylated genes.
 ...
PMID:Reexpression of epigenetically silenced AML tumor suppressor genes by SUV39H1 inhibition. 1988 40

A common feature shared between several human cancer-associated viruses, such as Epstein-Barr virus, Hepatitis B virus and Hepatitis C virus, and Human papillomavirus (HPV) is the ability to reduce the expression of cellular E-cadherin. Since E-cadherin is used by Langerhans cells to move through the stratified epithelium, its reduction may affect the efficiency by which the immune system responds to HPV infection and the length of persistent HPV infections. We observed that the E7 protein of this virus (HPV16) is most efficient at reducing E-cadherin levels. This E7 activity is independent of retinoblastoma protein or AP-2alpha degradation. Instead it is associated with augmentation of cellular DNA methyltransferase I (Dnmt1) activity. Significantly, inhibition of Dnmt activity re-established E-cadherin levels of the cells, presenting the possibility that similar epigenetic intervention clinically may be a way to re-establish the influx of Langerhans cells into infected epithelium to counteract HPV persistence.
 ...
PMID:Epigenetic repression of E-cadherin by human papillomavirus 16 E7 protein. 2012 56

E-cadherin, as a tumor suppressor, plays an important role for intercellular adhesion involved in metastasis. Although K-Ras is highly expressed in a variety of cancers, the regulation of E-cadherin expression by K-Ras in association with DNA methylation and cell metastasis has not been completely clarified. In this study, E-cadherin expression was repressed in 267B1/K-Ras human epithelial prostate cancer cells stably overexpressing K-Ras, resulting from hypermethylation of E-cadherin promoter as evidenced by methylation-specific polymerase chain reaction (PCR), bisulfite sequencing, real-time reverse transcription-PCR and western blot analysis. The increased level of DNA methyltransferase (DNMT) 3b in 267B1/K-Ras cells was reduced by small interfering RNA-mediated knockdown of k-ras, whereas DNMT1 and DNMT3a did not change regardless of K-Ras or 5-aza-2'-deoxycytidine (5'-AzaC) treatment. Furthermore, binding of DNMT3b to E-cadherin promoter was increased in 267B1/K-Ras cells but was reduced by 5'-AzaC, as revealed by chromatin immunoprecipitation assay, which was in agreement with cell aggregation and invasive mobilization of the cells. Hence, our data suggest that increased binding of DNMT3b to E-cadherin promoter region by K-Ras cause promoter hypermethylation for reduced expression of E-cadherin, leading to the decreased cell aggregation and increased metastasis of human prostate cancer cells overexpressing K-Ras.
 ...
PMID:Modulation of E-cadherin expression by K-Ras; involvement of DNA methyltransferase-3b. 2037 73

H3K9 methylation has been linked to a variety of biological processes including position-effect variegation, heterochromatin formation and transcriptional regulation. To further understand the function of H3K9 methylation, we have identified and characterized MPP8 as a methyl-H3K9-binding protein. MPP8 displays an elevated expression pattern in various human carcinoma cells, whereas knocking-down MPP8 results in the loss of cellular mesenchymal marker as well as the reduction of tumour cell migration and invasiveness, suggesting that MPP8 contributes to tumour progression. Following characterization demonstrates that MPP8 targets the E-cadherin gene promoter and modulates the expression of this key regulator of cell behaviour and tumour progression through its methyl-H3K9 binding. Furthermore, MPP8 interacts with H3K9 methyltransferases GLP and ESET, as well as DNA methyltransferase 3A. MPP8 knockdown decreases DNA methylation on E-cadherin CpG island attended by the loss of DNMT3A localization, indicating MPP8 also directs DNA methylation. Together, our results suggest a model by which MPP8 recognizes methyl-H3K9 marks and directs DNA methylation to repress tumour suppressor gene expression and, in turn, has an important function in epithelial-to-mesenchymal transition and metastasis.
 ...
PMID:Methyl-H3K9-binding protein MPP8 mediates E-cadherin gene silencing and promotes tumour cell motility and invasion. 2087 92


<< Previous 1 2 3 4 5 6 Next >>