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)

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

Epigenetic mechanisms, such as DNA methylation and histone deacetylation, may play a role in loss of estrogen receptor alpha (ER) expression in ER negative human breast cancer cells. Our previous studies showed that pharmacologic inhibition of these mechanisms using the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (AZA), and the histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), resulted in expression of functional ER mRNA and protein. Therefore, we sought to characterize the effects of a recently described HDAC inhibitor, Scriptaid, on cell growth and ER expression and function in ER negative human breast cancer cell lines. Scriptaid treatment of three ER negative cell lines, MDA-MB-231, MDA-MB-435 and Hs578t, resulted in significant growth inhibition and increased acetylation of H3 and H4 histone tails. Quantitative Real Time PCR showed 2000-20,000-fold increase of ER mRNA transcript in all three cell lines after 48 h of Scriptaid treatment. Further, dose dependent re-expression of an estrogen responsive gene, the progesterone receptor (PR), indicated that induced ER is functional. As seen with TSA and AZA, Scriptaid and AZA co-treatment was more effective in inducing ER than Scriptaid or AZA alone. In vivo analysis using a xenograft mouse model bearing MDA-MB-231 tumors showed decreased tumor growth following Scriptaid or TSA treatment. Our results indicate that the novel HDAC inhibitor, Scriptaid, inhibits tumor growth in vitro and in vivo and, in conjunction with AZA, acts to re-express functional ER. These data suggest that Scriptaid or related HDAC inhibitors are candidates for further study in breast cancer.
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PMID:A novel histone deacetylase inhibitor, scriptaid, enhances expression of functional estrogen receptor alpha (ER) in ER negative human breast cancer cells in combination with 5-aza 2'-deoxycytidine. 1462 Sep 13

Previous studies showed that progesterone receptor (PR), one of the hormone receptor superfamily, was only connected with the sex-correlated cancers such as breast cancer, endometrial cancer, prostate cancer, etc. This article deals with the PR gene in leukemia. We investigated the methylation status and the expression of the two different PR isoforms, PRA and PRB, in three leukemia cancer cell lines using methylation-specific polymerase chain reaction (MSP-PCR) and reverse transcription-PCR. The correlation of PR methylation and expression together with DNA methyltransferase (DNMT1) was further studied. We found that DNMT1 is required to maintain CpG methylation and aberrant gene silencing of PR gene in human leukemia cancer cells. The activity of 5-aza-2'-deoxycytidine in demethylation and gene reactivation may be through depleting cellular DNMT1 levels. In addition, extensive methylation of PRA and PRB was also observed in leukemia samples. Our results suggest that PR CpG island aberrant hypermethylation could be one molecular and genetic alteration in leukemia.
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PMID:Progesterone receptor gene inactivation and CpG island hypermethylation in human leukemia cancer cells. 1517 46

Progesterone plays an important role in the regulation of normal endometrium function by binding to progesterone receptor (PR). In endometrial cancer, however, PR is always down-regulated. Previous reports showed that methylation in the promoter region of the PR gene may be responsible for PRB isoform repression. However, the CpG islands in the exon region of the PR gene are much richer and longer than in the promoter region. We hypothesize that methylation in the exon region may also take part in the down-regulation of the PR gene. The methylation status of the first exon of the PR gene in endometrial cell cultures was investigated. Aberrant methylation patterns were observed in the first exon of PR gene, and the methylation density is correlated with the differentiation of different types of endometrial cancer cells. DNA methyltransferase (DNMT) and histone deacetylase inhibitor 5-aza-2'-deoxycytidine (ADC), as well as trichostatin A (TSA), which reverses PR gene expression, were also studied. A combination of ADC and TSA resulted in synergistic effects in inducing PR expression, down-regulation of DNMT1 and DNMT3A, and could also have antigrowth effect on endometrial cancer cells by inducing apoptosis.
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PMID:Down-regulation of the progesterone receptor by the methylation of progesterone receptor gene in endometrial cancer cells. 1755 66

Aberrant DNA methylation is an important molecular alteration commonly detected in various malignancies. Hypermethylation and expression silencing have been frequently found in multiple genes including those for steroid receptors, tumor suppressors, and DNA repair factors. Differential DNA methylation patterns are detected in type I and type II endometrial cancers, suggesting divergent epigenetic backgrounds and unique tumorigenic pathways. In this review, the implications of new findings in the field of epigenetics are discussed for endometrial cancer prevention, diagnosis, and treatment. DNA methylation-based assays may be explored as a useful adjunct diagnostic tool. Epigenetic modification reagents, including DNA methyltransferase and histone deacetylase inhibitors, when used alone or in combination with conventional chemotherapy, may be beneficial for endometrial cancer patients. Recent studies on epigenetic reactivation of the progesterone receptor provide a novel approach for re-sensitization of advanced, PR-negative endometrial cancers to progestational therapy.
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PMID:Epigenetic considerations for endometrial cancer prevention, diagnosis and treatment. 1769 7

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

Because DNA methyltransferase (DNMT) inhibitors like azacytidine and decitabine are known to be effective in the clinic for diseases like myelodysplastic syndromes that may result in part from transcriptional dysregulation due to epigenetic changes, there is interest in developing novel DNMT inhibitors that would be more effective and less toxic. The effects of one such agent, zebularine, which inhibits DNMT and cytidine deaminase, were assessed in two human breast cancer cell lines, MDA-MB-231 and MCF-7. Zebularine treatment inhibited cell growth in a dose and time dependent manner with an IC-50 of approximately 100 microM and 150 microM in MDA-MB-231 and MCF-7 cells, respectively, on 96 h exposure. This was associated with increased expression of p21, decreased expression of cyclin-D, and induction of S-phase arrest. At high doses zebularine induced changes in apoptotic proteins in a cell line specific manner manifested by alteration in caspase-3, Bax, Bcl2 and PARP cleavage. Like other DNMT inhibitors, zebularine decreased expression of DNMTs post-transcriptionally as well as expression of other epigenetic regulators like methyl CpG binding proteins and global acetyl H3 and H4 protein levels. Its capacity to reexpress epigenetically silenced genes in human breast cancer cells at low doses was confirmed by its ability to induce expression of estrogen and progesterone receptor mRNA in association with changes suggestive of active chromatin at the ER promoter as evidenced by ChIP. Finally, its effect in combination with other DNMT or HDAC inhibitors like decitabine or vorinostat was explored. The combination of 50 muM zebularine with decitabine or vorinostat significantly inhibited cell proliferation and colony formation in MDA-MB-231 cells compared with either drug alone. These findings suggest that zebularine is an effective DNMT inhibitor and demethylating agent in human breast cancer cell lines and potentiates the effects of other epigenetic therapeutics like decitabine and vorinostat.
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PMID:Effects of a novel DNA methyltransferase inhibitor zebularine on human breast cancer cells. 1945 41

Most breast carcinomas that are estrogen receptor (ER) and progesterone receptor (PR) positive respond initially to an endocrine therapy, but over time, they develop resistance (acquired hormone resistance). Others, however, fail to respond from the beginning (constitutive resistance). Overcoming hormone resistance is one of the major desirable aims in breast cancer treatment. Using the medroxyprogesterone acetate (MPA)-induced breast cancer mouse model, we have previously demonstrated that antiprogestin-responsive tumors show a higher expression level of PR isoform A (PRA) than PR isoform B (PRB), while tumors with constitutive or acquired resistance show a higher expression level of PRB. The aim of this study was to investigate whether PRA silencing in resistant tumors was due to PRA methylation. The CpG islands located in the PRA promoter and the first exon were studied by methylation-specific PCR (MSP) in six different tumors: two antiprogestin-responsive, two constitutive-resistant, and two with acquired resistance. Only in constitutive-resistant tumors, PRA expression was silenced by DNA methylation. Next, we evaluated the effect of a demethylating agent, 5-aza-2'-deoxycytidine, on PRA expression and antiprogestin responsiveness. In constitutive-resistant tumors, 5-aza-2'-deoxycytidine treatment in vitro and in vivo restored PRA expression and antiprogestin RU-486 responsiveness. Furthermore, high levels of DNA methyltransferase (Dnmts) 1 and 3b were detected in these tumors. In conclusion, our results suggest that methyltransferase inhibitors in combination with antiprogestins may be effective in the treatment of constitutive-resistant carcinomas with a high DNA methyltransferase level.
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PMID:Hypermethylation of the progesterone receptor A in constitutive antiprogestin-resistant mouse mammary carcinomas. 2044 May 53

The functional interaction of progesterone receptor (PR) isoforms PRA and PRB regulates myometrial transition from the resting state to excitation-contraction to initiate parturition. However, the regulatory mechanisms responsible for maintenance and functional alteration of the PRA and PRB expression levels during human pregnancy and term labor, respectively, remain unknown. Therefore, this study was designed to investigate whether and how epigenetic DNA modifications, specifically methylations, at the PRs' promoter regions contribute to the differential expression of PRA and PRB in laboring term myometrium of humans. Comparative analysis of PRA and PRB messenger RNA (mRNA) expression levels and accompanying changes in their promoters' methylation status was carried out using human myometrial samples from women undergoing singleton, term deliveries by cesarean section, either in the absence of labor (designated as NIL for not-in-labor) or in active labor (designated as IL for in labor). The PRA gene expression was shown to be elevated significantly during labor, while PRB gene expression was unaltered, and this differential expression was accompanied by decreased DNA methylation at the PRA promoter and not at the PRB promoter. In addition, labor-related decreased mRNA expression of the DNA methyltransferase (DNMT) family members DNMT1 and DNMT3a was found, however whether the increased expression of DNMTs directly supports the functional withdrawal of progesterone needs further investigation. Collectively, these data indicate that DNA methylation might represent an important epigenetic mechanism of labor-related differential expression of PRs, thereby mediating the biological process of functional PR withdrawal at term for parturition.
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PMID:Decreased DNA Methylations at the Progesterone Receptor Promoter A Induce Functional Progesterone Withdrawal in Human Parturition. 2440 75


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