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)

Prior studies have shown that the estrogen receptor (ER) gene is down-regulated in prostate cancer, but the mechanism of its inactivation is not known. We hypothesize that inactivation of the ER gene in prostate cancer is through promoter methylation. To test this hypothesis, we investigated the methylation status of the ER gene in prostate cancer cell lines, prostate cancer, and benign prostatic hyperplasia (BPH) tissues samples using the bisulfite genomic sequencing method. Our results show that the ER gene promoter was methylated in 100% (six of six) of the prostate cancer cell lines tested and all were accompanied by loss of ER mRNA expression. Treatment of these cell lines with demethylating agent 5-aza-2'-deoxycytidine restored ER mRNA expression in all of the ER-negative cell lines. In addition, elevated expression of DNA methyltransferase mRNA was found in all of the prostate cancer cell lines. Of the prostate tissue samples analyzed, 60% (6 of 10) in the BPH samples, 80% (8 of 10) in the low-grade cancer samples (grades I and II), and 95% (20 of 21) in the high-grade cancer samples (grades III-V) exhibited promoter methylation of the ER gene. The overall methylation levels in the cancer samples were higher than that in the BPH samples. The differences between the high-grade cancer samples and BPH samples were significant at all CpG sites. Only at three CpG sites were the differences significant between the low-grade cancer samples and BPH samples. This study presents the first evidence that ER gene is transcriptionally inactivated by DNA methylation in prostate cancer. Our data suggest that ER may be involved in the pathogenesis of prostate cancer, as well as BPH.
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PMID:Frequent methylation of estrogen receptor in prostate cancer: correlation with tumor progression. 1067 56

DNA methylation is an epigenetic modification that is associated with transcriptional silencing of gene expression in mammalian cells. Hypermethylation of the promoter CpG islands contributes to the loss of gene function of several tumor related genes, including estrogen receptor a (ER) and progesterone receptor (PR). Gene expression patterns are also heavily influenced by changes in chromatin structure during transcription. Indeed both the predominant mammalian DNA methyltransferase (DNMTI), and the histone deacetylases (HDACs) play crucial roles in maintaining transcriptionally repressive chromatin by forming suppressive complexes at replication foci. These new findings suggest that epigenetic changes might play a crucial role in gene inactivation in breast cancer. Further, inhibition of DNA methylation and histone deacetylation might be a therapeutic strategy in breast cancer, especially for those cancers with ER and PR negative phenotypes.
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PMID:Role of DNA methylation and histone acetylation in steroid receptor expression in breast cancer. 1150 78

Formation of transcriptional repression complexes such as DNA methyltransferase (DNMT) 1/histone deacetylase (HDAC) or methyl-CpG binding protein/HDAC is emerging as an important mechanism in silencing a variety of methylated tissue-specific and imprinted genes. Our previous studies showed that treatment of estrogen receptor (ER)-alpha-negative human breast cancer cells with the DNMT inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) led to ER mRNA and protein re-expression. Also, the HDAC inhibitor trichostatin A (TSA) could induce ER transcript about 5-fold. Here we show that 5-aza-dC alone induced ER transcript about 30-40-fold, and the addition of TSA elevated ER mRNA expression about 10-fold more in the human ER-negative breast cancer cell lines MDA-MB-231 and MDA-MB-435. Overall, the combination of 5-aza-dC and TSA induced a 300-400-fold increase in ER transcript. Restoration of estrogen responsiveness was demonstrated by the ability of the induced ER protein to elicit estrogen response element-regulated reporter activity from an exogenous plasmid as well as induce expression of the ER target gene, progesterone receptor. The synergistic activation of ER occurs concomitantly with markedly reduced soluble DNMT1 expression and activity, partial demethylation of the ER CpG island, and increased acetylation of histones H(3) and H(4). These data suggest that the activities of both DNMT1 and HDAC are key regulators of methylation-mediated ER gene silencing.
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PMID:Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. 1158 28

In this contribution, we review the limitations of the currently applied "standard" treatments for well-differentiated, non-medullary thyroid cancer (ThyrCa), and describe the molecular and cellular biologic basis of potential novel therapeutic modalities currently under study and/or development. Conventional therapy for ThyrCa consists of total/near-total thyroidectomy, radioiodine (RAI or 131I), and long-term thyroid hormone "suppressive" therapy (THST). RAI therapy remains the cornerstone of the "standard" management strategies for metastatic ThyrCa, and when administered under optimal conditions can achieve either eradication or long-term clinical "control" of the disease. Despite increasing sophistication in the protocols using 131I over the last 30 years, no significant down-trend has been observed in the annual mortality rate for this disease, a fact reflecting the existence of a "core" population of patients with RAI-"resistant" disease. The molecular basis for this phenomenon is believed to be the progressive tumoral de-differentiation over time, with loss of (or marked decrease in) the expression of cellular components responsible for iodine uptake, organification and retention. Adjuvant methods to RAI, such as radiosensitizers and lithium carbonate, provide only marginal additional therapeutic effect. Further, the role of non-RAI-based modalities, such as secondary extensive metastatectomies with curative intent, external beam radiotherapy, and cytotoxic chemotherapy (mainly with doxorubicin-based regimens) has been unfortunately limited to highly selected cases. Palliative methods for acute clinical management of widely metastatic ThyrCa are also presented, along with anecdotal evidence for the potential therapeutic role for octreotide and its radiolabeled therapeutic peptide analogs, selective estrogen receptor modulators (SERM's), as well as bisphosphonates. Translational "bench-to-bedside" research has recently led to the identification of the transcriptional machinery as a valid target for future therapeutic efforts in ThyrCa. Indeed, pre-clinical studies with a variety or agents that affect the rate of thyroid-specific gene transcription, i.e. retinoids, DNA methyltransferase inhibitors, and histone deacetylase inhibitors, have shown their potential for induction of re-differentiation, growth inhibition, promotion of apoptosis and cell cycle regulation. These concerted genomic effects of the above compounds will probably yield novel types of therapies in the clinical arena, especially for RAI-non-avid tumors. Retinoid analogs have already been used in pilot studies in ThyrCa patients with limited success. These re-differentiating agents have raised our expectations for a type of therapy for this malignancy based on a solid molecular rationale, while future progress in the domains of tissue-targeted gene therapy and anti-angiogenesis is eagerly awaited.
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PMID:Metastatic thyroid cancer unresponsive to conventional therapies: novel management approaches through translational clinical research. 1247 92

Recent studies have shown that changes in epigenetic regulation, such as DNA methylation and histone acetylation, are associated with silencing of the estrogen receptor a (ER) gene in ER-negative human breast cancer cells. Treatment of these cells with the general DNMT inhibitor, 5-aza-2'deoxycytidine, led to reactivation of functional ER protein. This study addresses the hypothesis that specific inhibition of the maintenance DNA methyltransferase, DNMT1, by antisense oligonucleotides (DNMT1 ASO) is sufficient to re-express the ER gene in ER-negative human breast cancer cell lines. MDA-MB-231 and Hs578t cells were transfected with 100 nM and 150 nM DNMT1 ASO respectively for three consecutive days and evidence of DNMT1 downregulation and functional ER re-expression was sought. Significant growth reduction was observed within 48 hr and persisted after 96 hr. DNMT1 expression was blocked after exposure to DNMT1 ASO as detected by RT-PCR, Western blot and enzymatic assay whereas a mutant DNMT1 ASO had little effect. This was associated with enhanced ER mRNA and protein expression and restoration of estrogen responsiveness in MDA-MB-231 cells as demonstrated by the ability of the induced ER protein to elicit ERE-regulated reporter activity from a luciferase reporter construct. Methylation specific PCR showed that the ER CpG island was minimally demethylated, suggesting that other epigenetic events, introduced by specific DNMT1 inhibition, might also be involved in ER re-expression. Our results suggest that specific inhibition of DNMT1 expression alone is sufficient to re-express ERa in human breast cancer cell lines.
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PMID:Specific inhibition of DNMT1 by antisense oligonucleotides induces re-expression of estrogen receptor-alpha (ER) in ER-negative human breast cancer cell lines. 1461 26

Non-ortho polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) are ubiquitous environmental contaminants that exert their toxicity mostly through activation of the aryl-hydrocarbon receptor (AhR), and are referred to as AhR agonists. The objective was to study, by real time reverse-transcriptase-polymerase chain reaction (RT-PCR), the effects of postnatal exposure to a reconstituted mixture of AhR agonists present in breast milk (3 non-ortho PCBs, 6 PCDDs, and 7 PCDFs, referred to here-in-after as AhRM) on mRNA expression of estrogen receptor (ERalpha), enzymes involved with the metabolism of estrogens [catechol-o-methyltransferase (Comt), cytochrome P450 (Cyp)1A1, 1B1 and 2B1], and DNA methyltransferase-1 (Dnmt1), in brain areas, liver and uterus of immature female rats. Neonates were exposed by gavage during postnatal day (PND) 1-20 with dosages equivalent to 1, 10, 100, and 1000 times the estimated average human exposure level, and were sacrificed at PND 21. None of the end points were affected in uterine cross-sections, or in samples of uterine tissue layers collected by laser capture microdissection. At 1000x, the AhRM reduced Dnmt1 mRNA abundance to 28% and 32% of control in the liver and hypothalamus, respectively. In the brain, Cyp1A1 was increased (409%) but ERalpha was reduced (66%). Similarly, mRNA abundance for Comt isoforms was reduced in the liver (45%) and brain areas (55-70%). AhRM at 100x, the lowest effective dose, exerted a 220% increase in brain cortex Comt [membrane bound (Mb)], a 219% increase in hepatic Cyp1B1, and a 63% decrease in hepatic Comt (soluble (S)+Mb). These results support the possibility that early exposure to environmental contaminants could lead to effects mediated by changes in DNA methylation and/or estrogen metabolism and signaling.
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PMID:Comparisons of brain, uterus, and liver mRNA expression for cytochrome p450s, DNA methyltransferase-1, and catechol-o-methyltransferase in prepubertal female Sprague-Dawley rats exposed to a mixture of aryl hydrocarbon receptor agonists. 1585 27

Cigarette smoking is inversely associated with endometrial cancer risk. Smoking is proposed to decrease risk, in large part, through its anti-estrogenic effects in the uterus. In addition, cigarette smoke is a major source of alkylation damage. The O6-methylguanine DNA methyltransferase (MGMT) gene is responsible for repairing alkylation DNA damage and also has a role in inhibiting estrogen receptor-mediated cell proliferation. Because of MGMT's dual functions, it is a strong candidate gene for endometrial cancer. We assessed the two functional polymorphisms, the Leu84Phe and Ile143Val, in relation to endometrial cancer risk in a nested case-control study within the Nurses' Health Study (cases = 456, controls = 1134). Compared with the 84Leu/Leu genotype, the Phe carriers had a significantly decreased risk of endometrial cancer [odds ratio (OR), 0.72; 95% confidence interval (CI), 0.53-0.96]. We did not observe an association between the Ile143Val polymorphism and endometrial cancer risk overall. We observed a significant multiplicative interaction between the Ile143Val polymorphism and pack-years of smoking on endometrial cancer risk (P, interaction, 0.04); the inverse association of pack-years with endometrial cancer risk was limited to the 143Val carriers (P, trend, 0.01). Compared with women who had the Ile/Ile genotype and never smoked, the 143Val carriers who had >30 pack-years of smoking had a significantly decreased risk of endometrial cancer (OR, 0.41; 95%CI, 0.19-0.86). These data suggest that these two polymorphisms may influence endometrial cancer risk.
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PMID:Polymorphisms in O6-methylguanine DNA methyltransferase and endometrial cancer risk. 1677 93

Tamoxifen, a synthetic triphenyl-ethylene compound, is a member of a class of anticancer drugs known as selective estrogen receptor modulators. It may block tumor growth by mimicking estrogen and binding to the estrogen receptors, preventing cancerous growth. Clinical studies have demonstrated that a combination chemo/hormonal therapy regimen with tamoxifen and O(6)-alkylating drugs increased the tumor response rate in cancer patients. The mechanism of action of this combined regimen remains undefined. In this study, we demonstrated that treatment of human colorectal HT-29 carcinoma cells with tamoxifen decreased the repair activity and expression level of O(6)-methylguanine DNA methyltransferase (MGMT) protein in a concentration- and time-dependent manner. This inhibition was also shown in other malignant human cells, regardless of their estrogen receptor status. Furthermore, MGMT inactivation by tamoxifen was associated with a significantly increased susceptibility of cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). No alteration in MGMT mRNA levels was observed in tamoxifen-treated cells. The half-life of MGMT protein was markedly decreased in the presence of tamoxifen. Tamoxifen-induced MGMT degradation could be blocked by MG-132, a proteasome inhibitor. An increased level of ubiquitinated MGMT protein was found after tamoxifen treatment. We conclude that tamoxifen decreased the MGMT protein level by accelerating protein degradation through the ubiquitin-dependent proteasomal pathway. These findings provide a strong rationale for combined chemo/hormonal therapy with tamoxifen and BCNU in the treatment of human cancers.
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PMID:Tamoxifen accelerates proteasomal degradation of O6-methylguanine DNA methyltransferase in human cancer cells. 1759 6

Bexarotene has demonstrated chemopreventive and therapeutic efficacy towards mouse lung tumors. Using specimens from our published study that demonstrated the efficacy of bexarotene, we report herein its ability to modulate mRNA expression of genes in both lung and lung tumors. Strain A/J mice were administered vinyl carbamate to induce lung tumors. This was followed by 200 mg/kg body weight of bexarotene administered by oral gavage during Wks 4-25 or 23-25. The mice were sacrificed at Wk 25. The expression of 26 genes was decreased in lung tumors, whereas only two genes, Apolipoprotein D and CYP26b, had their mRNA expression increased by bexarotene. Genes with increased mRNA expression in untreated lung tumors include: epiregulin and kininogen-1 (increased by more than 40-fold) and Caspase-3, Cyclin D1, DNA methyltransferase 3a (Dnmt-3a), E-prostanoid 3 receptor (EP3), c-myc, surfactant protein-C, and survivin (increased by 1.7- to 3.6-fold). Bexarotene decreased the mRNA expression of Caspase-3, Dnmt-3a, EP3, and survivin, as well as the expression of the Cyclin E1, estrogen receptor-alpha, and iNOS genes. Bexarotene had a greater effect in decreasing the expression of Caspase-3, Cyclin E1, Dnmt-3a, EP3, iNOS, and survivin, when administered to mice with established tumors than when administered to mice while tumors were emerging. In summary, bexarotene modulated mRNA expression of genes in mouse lung tumors, being more effective in established tumors than in emerging tumors, suggesting that modulation of expression could be useful as a biomarker for the therapeutic and chemopreventive activity of the drug, especially in established tumors.
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PMID:Modulation by bexarotene of mRNA expression of genes in mouse lung tumors. 1784 52

In breast cancer, approximately one-third of tumors express neither the estrogen receptor (ERalpha) nor estrogen-regulated genes such as the progesterone receptor gene (PR). Our study provides new insights into the mechanism allowing hormone-activated expression of ERalpha target genes silenced in ERalpha-negative mammary tumor cells. In cell lines derived from ERalpha-negative MDA-MB231 cells, stable expression of different levels of ERalpha from a transgene did not result in transcription of PR. A quantitative comparative analysis demonstrates that inhibiting DNA methyltransferases using 5-aza-2'-deoxycytidine or specific disruption of DNMT1 by small interfering RNAs and treatment with the histone-deacetylase inhibitor trichostatin A enabled ERalpha-mediated hormone-dependent expression of endogenous PR. We show that demethylation of a CpG island located in the first exon of PR was a prerequisite for ERalpha binding to these regulatory sequences. Although not a general requirement, DNA demethylation is also necessary for derepression of a subset of ERalpha target genes involved in tumorigenesis. PR transcription did not subsist 4 days after removal of the DNA methyltransferase blocking agents, suggesting that hormone-induced expression of ERalpha target genes in ERalpha-negative tumor cells is transient. Our observations support a model where an epigenetic mark confers stable silencing by precluding ERalpha access to promoters.
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PMID:Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells. 1831 49


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