Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

O6-Methylguanine-DNA methyltransferase (MGMT) in human neoplastic tissues has been associated with tumor resistance to alkylating agents. The purposes of this study are to assay MGMT activity in ovarian cancers and to correlate MGMT titers with chemotherapy response to cisplatin and cyclophosphamide in patients with ovarian cancer. MGMT levels were determined by a biochemical assay of tumor tissues from 20 patients with ovarian malignancy. The clinical stages of the patients studied were 4 in Stage I, 2 in Stage II, 12 in Stage III, and 2 in Stage IV. The mean MGMT activity was 34 +/- 9 fmole methyls transferred/mg protein. Among 13 patients with tumor MGMT levels more than 10 fmole/mg protein, 10 (77%) of them were resistant to postoperative combination chemotherapy. In the remaining 7 patients with low MGMT titer of less than 10 fmole/mg protein, a majority (71%) had a complete response (P < 0.10). These preliminary results indicate that ovarian cancer has detectable MGMT activity, and this activity is possibly correlated with treatment failure to a postoperative cisplatin regimen.
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PMID:O6-methylguanine-DNA methyltransferase in ovarian malignancy and its correlation with postoperative response to chemotherapy. 831 34

The expression of different genes potentially involved in DNA repair and in cell responses to chemotherapy was evaluated in 33 previously untreated ovarian cancer patients. In biopsies of the same patients the expression of repair genes O6-methylguanine DNA methyltransferase (MGMT), 3-methyladenine DNA glycosylase (MAG), ERCC1, MDR-1, DNA topoisomerase I, DNA topoisomerase IIalpha, and glutathione S-transferase-pi (GST-pi) was assessed by Northern blot analysis. No direct statistical correlation was found between the expression of these genes and the response to chemotherapy (mainly platinum-based with or without doxorubicin and cyclophosphamide). Univariate analysis showed a weak negative correlation (P = 0.037) between the expression of ERCC1 and mortality, whereas no statistically significant correlation was found for other parameters. The MDR-1 gene encoding for the P-glycoprotein P-170 was mostly undetectable in these patients (as assessed by Northern blotting), whereas relatively high levels of MAG and MGMT were found in the majority of patients. A statistically significant correlation was found between the expression of DNA topoisomerase I and the expression of either ERCC1 (P = 0.0026) or GST-pi (P = 0.0279).
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PMID:Expression of genes of potential importance in the response to chemotherapy and DNA repair in patients with ovarian cancer. 910 2

Small interfering RNAs (siRNAs) are newly identified molecules shown to silence genes via targeted mRNA degradation. In this study, we used specific siRNAs as a tool to probe the relationship between two DNA methyltransferase genes, DNMT3b and DNMT1, in the maintenance of DNA methylation patterns in the genome. Levels of DNMT3b or DNMT1 mRNAs and proteins were markedly decreased (up to 80%) on transfecting these siRNAs into the ovarian cancer cell line CP70. The resulting RNA interference showed differential effects on DNA demethylation and gene reactivation in the treated cells. The DNMT1 siRNA treatment led to a partial removal of DNA methylation from three inactive promoter CpG islands, TWIST, RASSF1A, and HIN-1, and restored the expression of these genes. This epigenetic alteration appeared less effective in cells transfected with DNMT3b siRNA. However, the combined treatment of DNMT3b and DNMT1 siRNAs greatly enhanced this demethylation effect, producing 7-15-fold increases in their expression. We also used a microarray approach to examine this RNA interference on 8640 CpG island loci in CP70 cells. The combined siRNA treatment had a greater demethylation effect on 241 methylated loci and selected repetitive sequences than that of the single treatment. Our data thus suggest that whereas DNMT1 plays a key role in methylation maintenance, DNMT3b may act as an accessory to support the function in CP70 cells. This study also shows that siRNA is a powerful tool for interrogating the mechanisms of DNA methylation in normal and pathological genomes.
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PMID:Double RNA interference of DNMT3b and DNMT1 enhances DNA demethylation and gene reactivation. 1455 86

We have determined the methylation frequencies of 24 CpG islands of genes associated with DNA damage responses or with ovarian cancer in 106 stage III/IV epithelial ovarian tumors. We have analyzed this data for whether there is evidence of a CpG island methylator phenotype or associations of CpG island methylation with response to chemotherapy in advanced ovarian cancer. Frequent methylation was observed for OPCML, DCR1, RASSF1A, HIC1, BRCA1, and MINT25 (33.3%, 30.7%, 26.4%, 17.3%, 12.3%, and 12.0%, respectively), whereas no methylation was observed for APAF-1, DAPK, FANCF, FAS, P14, P21, P73, SOCS-3, and SURVIVIN. The remaining genes showed only a low frequency of methylation, <10%. Unsupervised gene shaving identified a nonrandom pattern of methylation for OPCML, DCR1, RASSF1A, MINT25, HIC1, and SFRP1, supporting the concept of concordant methylation of these genes in ovarian cancer. Methylation of at least one of the group of genes involved in DNA repair/drug detoxification (BRCA1, GSTP1, and MGMT) was associated with improved response to chemotherapy (P = 0.013). We have examined the frequency of a polymorphism in the DNA methyltransferase gene DNMT3b6, which has been previously reported to affect gene transcription and cancer risk. The genetic polymorphism in the DNMT3b6 gene promoter (at position -149) is not significantly associated with the concordant methylation observed, but is weakly associated with the overall frequency of methylation at the genes examined (P = 0.04, n = 56). This supports the hypothesis that genetic factors affecting function of DNMT genes may underlie the propensity of tumors to acquire aberrant CpG island methylation.
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PMID:CpG island methylation of DNA damage response genes in advanced ovarian cancer. 1620 69

Opioid binding protein/cell adhesion molecule-like gene (OPCML), a recently identified tumor-suppressor, is frequently inactivated by allele loss and CpG island promoter methylation in epithelial ovarian cancer. Since elevated activation of the RAS signaling pathway, including overexpression of HER-2/neu and mutations of RAS and BRAF, is common in human ovarian carcinoma, we examined the cellular effect of oncogenic RAS on the expression status of OPCML in a genetically defined human ovarian cancer model. Our study revealed that RAS(V12)-mediated oncogenic transformation was accompanied by a concomitant loss of OPCML expression. Methylation-sensitive PCR analysis showed that the OPCML promoter was hypermethylated in RAS-transformed human ovarian epithelial cells (T29H) and that treatment with the DNA methyltransferase inhibitor 5'-aza-2'-deoxycytidine promoted demethylation of the OPCML promoter and restored OPCML expression in T29H cells. Furthermore, suppression of oncogenic RAS activity by stable siRNA specific for HRAS(V12) led to the demethylation and re-expression of OPCML in T29H cells, demonstrating that oncogenic RAS activity is directly responsible for the observed OPCML promoter hypermethylation and epigenetic gene silencing of OPCML. Taken together, our study suggests that elevation of the RAS signaling pathway may play an important role in epigenetic inactivation of OPCML in human epithelial ovarian cancer.
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PMID:RAS-mediated epigenetic inactivation of OPCML in oncogenic transformation of human ovarian surface epithelial cells. 1638 11

The claudin (CLDN) genes encode a family of proteins involved in the formation and function of tight junctions. CLDN gene expression is frequently altered in several human cancers, and in particular, CLDN3 and CLDN4 are commonly overexpressed in ovarian cancer. However, the mechanisms leading to the deregulation of these genes in cancer remain unclear. In the present study, we have examined the CLDN3 promoter and have identified a minimal region containing an Sp1 site crucial for its activity. In addition, we find that the CLDN3 promoter is regulated through epigenetic processes. Cells that express high levels of CLDN3 exhibit low DNA methylation and high histone H3 acetylation of the critical CLDN3 promoter region, and the reverse is observed in cells that do not express this gene. CLDN3-negative cells can be induced to express CLDN3 through treatment with DNA methyltransferase or histone deacetylase inhibitors. Interestingly, in vitro binding experiments, as well as chip assays show that Sp1 binds the unmethylated promoter much more efficiently, providing a mechanism for CLDN3 silencing in non-expressing cells. Finally, siRNA-mediated knockdown of Sp1 led to a significant decrease of CLDN3 expression at both the mRNA and protein levels, demonstrating a crucial role for this transcription factor in the regulation of CLDN3. Our data provide a basis for CLDN3 expression in ovarian cancer cells, as well as a mechanism for the silencing of this promoter in tumors lacking expression of claudin-3.
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PMID:Regulation of the CLDN3 gene in ovarian cancer cells. 1798 52

The cancer stem cell hypothesis posits that malignant growth arises from a rare population of progenitor cells within a tumor that provide it with unlimited regenerative capacity. Such cells also possess increased resistance to chemotherapeutic agents. Resurgence of chemoresistant disease after primary therapy typifies epithelial ovarian cancer and may be attributable to residual cancer stem cells, or cancer-initiating cells, that survive initial treatment. As the cell surface marker CD133 identifies cancer-initiating cells in a number of other malignancies, we sought to determine the potential role of CD133+ cells in epithelial ovarian cancer. We detected CD133 on ovarian cancer cell lines, in primary cancers and on purified epithelial cells from ascitic fluid of ovarian cancer patients. We found CD133+ ovarian cancer cells generate both CD133+ and CD133- daughter cells, whereas CD133- cells divide symmetrically. CD133+ cells exhibit enhanced resistance to platinum-based therapy, drugs commonly used as first-line agents for the treatment of ovarian cancer. Sorted CD133+ ovarian cancer cells also form more aggressive tumor xenografts at a lower inoculum than their CD133- progeny. Epigenetic changes may be integral to the behavior of cancer progenitor cells and their progeny. In this regard, we found that CD133 transcription is controlled by both histone modifications and promoter methylation. Sorted CD133- ovarian cancer cells treated with DNA methyltransferase and histone deacetylase inhibitors show a synergistic increase in cell surface CD133 expression. Moreover, DNA methylation at the ovarian tissue active P2 promoter is inversely correlated with CD133 transcription. We also found that promoter methylation increases in CD133- progeny of CD133+ cells, with CD133+ cells retaining a less methylated or unmethylated state. Taken together, our results show that CD133 expression in ovarian cancer is directly regulated by epigenetic modifications and support the idea that CD133 demarcates an ovarian cancer-initiating cell population. The activity of these cells may be epigenetically detected and such cells might serve as pertinent chemotherapeutic targets for reducing disease recurrence.
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PMID:Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. 1883 86

Epigenetic silencing of tumor suppressor genes is a new focus of investigation in the generation and proliferation of carcinomas. Secreted protein acidic and rich in cysteine (SPARC) is reportedly detrimental to the growth of ovarian cancer cells and has been shown to be epigenetically silenced in several cancers. We hypothesized that SPARC is downregulated in ovarian cancer through aberrant promoter hypermethylation. To that end, we analyzed SPARC expression in ovarian cancer cell lines and investigated the methylation status of the Sparc promoter using methylation-specific polymerase chain reaction. Our results show that SPARC mRNA expression is decreased in three (33%) and absent in four (44%) of the nine ovarian cancer cell lines studied, which correlated with hypermethylation of the Sparc promoter. Treatment with the demethylating agent 5-aza-2'-deoxycytidine rescued SPARC mRNA and protein expression. Addition of exogenous SPARC, as well as ectopic expression by an adenoviral vector, resulted in decreased proliferation of ovarian cancer cell lines. Investigation of primary tumors revealed that the Sparc promoter is methylated in 68% of primary ovarian tumors and that the levels of SPARC protein decrease as the disease progresses from low to high grade. Lastly, de novo methylation of Sparc promoter was shown to be mediated by DNA methyltransferase 3a. These results implicate Sparc promoter methylation as an important factor in the genesis and survival of ovarian carcinomas and provide new insights into the potential use of SPARC as a novel biomarker and/or treatment modality for this disease.
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PMID:Aberrant promoter methylation of SPARC in ovarian cancer. 1917 97

Ovarian cancer is the leading cause of death among gynecological cancers. It is now recognized that in addition to genetic alterations, epigenetic mechanisms, such as DNA methylation, histone modifications and nucleosome remodeling, play an important role in the development and progression of ovarian cancer by modulating chromatin structure, and gene and miRNA expression. Furthermore, epigenetic alterations have been recognized as useful tools for the development of novel biomarkers for diagnosis, prognosis, therapeutic prediction and monitoring of diseases. Moreover, new epigenetic therapies, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors, have been found to be a potential therapeutic option, especially when used in combination with other agents. Here we discuss current developments in ovarian carcinoma epigenome research, the importance of the ovarian carcinoma epigenome for development of diagnostic and prognostic biomarkers, and the current epigenetic therapies used in ovarian cancer.
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PMID:Epigenomics and ovarian carcinoma. 2070 43

Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Diagnosis usually occurs after metastatic spread, largely reflecting vague symptoms of early disease combined with lack of an effective screening strategy. Epigenetic mechanisms of gene regulation, including DNA methylation, are fundamental to normal cellular function and also play a major role in carcinogenesis. To elucidate the biological and clinical relevance of DNA methylation in ovarian cancer, we conducted expression microarray analysis of 39 cell lines and 17 primary culture specimens grown in the presence or absence of DNA methyltransferase (DNMT) inhibitors. Two parameters, induction of expression and standard deviation among untreated samples, identified 378 candidate methylated genes, many relevant to TGF-beta signaling. We analyzed 43 of these genes and they all exhibited methylation. Treatment with DNMT inhibitors increased TGF-beta pathway activity. Hierarchical clustering of ovarian cancers using the 378 genes reproducibly generated a distinct gene cluster strongly correlated with TGF-beta pathway activity that discriminates patients based on age. These data suggest that accumulation of age-related epigenetic modifications leads to suppression of TGF-beta signaling and contributes to ovarian carcinogenesis.
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PMID:Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer. 2115 26


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