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)

Chronic stress is associated with more rapid tumor progression, and recent evidence suggests that stress may contribute to social and ethnic disparities in the incidence and mortality of breast cancer. We evaluated the p53(+/-) FVB/N mouse as a model to investigate effects of chronic social stress on mammary gland development, gene expression, and tumorigenesis. We individually housed (IH) wild-type and p53(+/-) female FVB/N mice, starting at weaning. At 14 weeks of age, both wild-type and p53(+/-) IH mice showed strikingly reduced mammary development compared with group-housed (GH) controls, with IH mice having significantly fewer preterminal end buds. This morphologic difference was not reflected in levels of mammary transcripts for estrogen receptor-alpha or progestin receptor. However, IH increased levels of mRNA for the kisspeptin receptor in the medial preoptic area of the hypothalamus, associated with reduced duration of estrous cycles. Furthermore, IH altered mammary transcripts of genes associated with DNA methylation; transcripts for methyl-binding protein 2 and DNA methyltransferase 3b (DNMT3b), but not DNMT1 and DNMT3a, were reduced in IH compared with GH females. Interestingly, the glands of p53(+/-) females showed reduced expression of all these mediators compared with wild-type females. However, contrary to our initial hypothesis, IH did not increase mammary tumorigenesis. Rather, p53(+/-) GH females developed significantly more mammary tumors than IH mice. Together, these data suggest that social isolation initiated at puberty might confound studies of tumorigenesis by altering mammary development in mouse models.
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PMID:Social isolation reduces mammary development, tumor incidence, and expression of epigenetic regulators in wild-type and p53-heterozygotic mice. 2042 36

The DNA-damaging drug doxorubicin (Dox) induces cell senescence at concentrations significantly lower than those required for induction of apoptosis. At low Dox concentrations, tumor suppressor p53 is activated, which enhances the expression of p21(Waf1/Cip1) (p21). At high concentrations, Dox activates p53 leading to apoptosis without enhancing p21 expression. The underlying mechanisms and factors that govern the differential effects of Dox in inducing senescence and apoptosis are unclear. Here, we report that the DNA methyltransferase (DNMT) DNMT3a was upregulated by Dox especially at concentrations that induced apoptosis in HCT116 colorectal cancer cells, and this process was regulated by p53. Meanwhile, p21 expression was significantly upregulated at senescence-inducing concentrations and kept low on treatment with apoptosis-inducing concentrations of Dox. The differential expression of DNMT3a and p21 in response to Dox suggests that DNMT3a may be a key factor in switches between Dox-induced senescence and apoptosis. Moreover, when DNMT3a was silenced, treatment of HCT116 cells with apoptosis-inducing concentration of Dox increased the percentage of cells undergoing senescence, accompanied by upregulation of p21. Contrarily, senescence-inducing concentration of Dox promoted apoptosis rate, and p21 expression was repressed. Surprisingly, no changes in DNA methylation status at p21 promoter were detected at either ranges of Dox, although DNMT3a and HDAC1 were recruited to p21 promoter at apoptosis-inducing Dox concentration, where they were present in the same complex. Overall, these data demonstrate that DNMT3a impacts the expression of p21 and plays a role in determining the Dox-induced senescence and apoptosis in HCT116 cells.
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PMID:DNMT3a plays a role in switches between doxorubicin-induced senescence and apoptosis of colorectal cancer cells. 2047 58

In this study, we reviewed epigenetic therapy of lymphomas using histone deacetylase inhibitors (HDACi), a promising new class of antineoplastic agents. Epigenetic therapy, a new therapeutic concept, consists of the use of HDACi and or DNA methyltransferase inhibitors (DNMTi). We conducted a comprehensive review of the literature for antitumour activity of HDACi and its mechanism of action. HDACi modify the expression of several genes related to cancer development, which can result in antineoplastic activity. To elucidate the benefits of HDACi in lymphoma treatment, we discuss the crucial interplay between BCL6, p53 and STAT3. Activated B-cell (ABC) diffuse large cell lymphoma (DLCL) is increasingly being recognised as an unfavourable and frequently therapy-refractory lymphoma. We discuss the fundamental causative role of the STAT3 oncogene in ABC type DLCL. STAT3 can be effectively suppressed by several HDACi, a promising treatment for this difficult subtype of DLCL. On the other hand, various HDACi can repress the germinal-centre B Cell (GCB) type DLCL by virtue of their inhibition of the BCL6 oncogene, usually expressed in this particular subtype. We summarise the results of recent clinical trials with HDACi such as romidepsin, panobinostat, MGCD-0103, entinostat, curcumin, JAK2 inhibitor TG101348, and valproic acid that have shown preliminary activity in recurrent and refractory lymphomas. The unique mechanism of action of HDACi makes them very attractive agents to pursue in combination. Several ongoing trials are already exploring HDACi combinations in various types of cancers. Their role in front-line management remains to be determined.
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PMID:Epigenetic therapy of lymphoma using histone deacetylase inhibitors. 2053 95

Epigenetic modifications are involved in the initiation and progression of cancer. Expression patterns and activity of DNA methyltransferases (DNMTs) are strictly controlled in normal cells, however, regulation of these enzymes is lost in cancer cells due to unknown reasons. Cancer therapies which target DNMTs are promising treatments of hematologic cancers, but they lack effectiveness in solid tumors. Solid tumors exhibit areas of hypoxia and hypoglycaemia due to their irregular and dysfunctional vasculature, and we previously showed that hypoxia reduces global DNA methylation. Colorectal carcinoma (CRC) cells (HCT116 and 379.2; p53+/+ and p53-/-, respectively) were subjected to ischemia (hypoxia and hypoglycaemia) in vitro, and levels of DNMTs were assessed. We found a significant decrease in mRNA for DNMT1, DNMT3a and DNMT3b, and similar reductions in DNMT1 and DNMT3a protein levels were detected by western blotting. In addition, total activity levels of DNMTs (as measured by an ELISA-based DNMT activity assay) were reduced in cells exposed to hypoxic and hypoglycaemic conditions. Immunofluorescence of HCT116 tumor xenografts demonstrated an inverse relationship between ischemia (as revealed by carbonic anhydrase IX staining) and DNMT1 protein. Bisulfite sequencing of the proximal promoter region of p16INK4a showed a decrease in 5-methylcytosine following in vitro exposure to ischemia. These studies provide evidence for the down-regulation of DNMTs and modulation of methylation patterns by hypoxia and hypoglycaemia in human CRC cells, both in vitro and in vivo. Our findings suggest that ischemia, either intrinsic or induced through the use of anti-angiogenic drugs, may influence epigenetic patterning and hence tumor progression.
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PMID:Ischemia dysregulates DNA methyltransferases and p16INK4a methylation in human colorectal cancer cells. 2054 77

Tumor protein p53-induced nuclear protein 1 (TP53INP1) is a well known stress-induced protein that plays a role in both cell cycle arrest and p53-mediated apoptosis. Loss of TP53INP1 expression has been reported in human melanoma, breast carcinoma, and gastric cancer. However, TP53INP1 expression and its regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Our findings are in agreement with previous reports in that the expression of TP53INP1 was downregulated in 28% (10/36 cases) of ESCC lesions, and this was accompanied by significant promoter methylation. Overexpression of TP53INP1 induced G1 cell cycle arrest and increased apoptosis in ESCC cell lines (EC-1, EC-109, EC-9706). Furthermore, our study showed that the oncoprotein c-Myc bound to the core promoter of TP53INP1 and recruited DNA methyltransferase 3A to methylate the local promoter region, leading to the inhibition of TP53INP1 expression. Our findings revealed that TP53INP1 is a tumor suppressor in ESCC and that c-Myc-mediated DNA methylation-associated silencing of TP53INP1 contributed to the pathogenesis of human ESCC.
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PMID:c-Myc inhibits TP53INP1 expression via promoter methylation in esophageal carcinoma. 2121 56

To enhance the potency of current EGFR inhibitors, we developed a novel strategy that seeks to confer them an additional DNA damaging function, leading to the design of drugs termed combi-molecules. ZRS1 is a novel combi-molecule that contains an EGFR tyrosine kinase targeting quinazoline arm and a methyltriazene-based DNA damaging one. We examined its effect on human tumor cell lines with varied levels of EGFR and O6-methylguanine DNA methyltransferase (MGMT). ZRS1 was more potent than the clinical methylating agent temozolomide in all cell lines, regardless of their MGMT status. However, its potency was in the same range as or less than that of Iressa, an EGFR inhibitor, against MGMT-proficient cells. In the MGMT-deficient or in MGMT-proficient cells exposed to the MGMT inhibitor O6-benzylguanine, its potency was superior to that of Iressa and temozolomide or a temozolomide+Iressa combination. Cell signaling analysis in A549 (MGMT(+)) and A427 (MGMT(-)) showed that ZRS1 strongly inhibited EGFR phosphorylation and related signaling pathways. In addition, the p53 pathway was activated by DNA damage in both cell lines, but apoptosis was significantly more pronounced in A427 cells. Using MGMT shRNA to block endogenous MGMT protein expression in A549 resulted in significant sensitization to ZRS1. Furthermore, transfection of MGMT into A427 greatly decreased the potency of ZRS1. These results conclusively show that MGMT is a critical molecular determinant for the full-blown potency of the dual EGFR-DNA targeting combi-molecule.
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PMID:MGMT is a molecular determinant for potency of the DNA-EGFR-combi-molecule ZRS1. 2126 32

In human pancreatic cancers, promoter CpG island hypermethylation is observed in both benign and malignant tumors. It is thought that silencing of key growth-controlling genes by promoter hypermethylation may play a role in pancreatic oncogenesis. We have shown previously that sufficient levels of DNA methyltransferase (Dnmt) 1 expression are required for the development of murine intestinal tumors. Here, we report the results of a large-scale triple cross (progeny n = 761) between Apc(Min/+), Trp53(-/-) and Dnmt1 hypomorphic mice to investigate the role of Dnmt levels in the Apc(Min/+), Trp53(-/-) mouse models of acinar cell pancreatic cancer. Mutations of both APC and TP53 are observed in human pancreatic cancer. We found that tumor burden, but not tumor size, is significantly reduced with decreasing Dnmt1 levels, suggesting that DNA methylation is involved in pancreatic tumorigenesis in this mouse model. Detailed analyses showed that the reduction in tumor burden is the result of a decrease in both early- and late-stage lesions. We observed decreased levels of DNA methylation at candidate genes in the normal pancreas of Dnmt1 hypomorphic mice. Some of these genes showed increased methylation associated with tumorigenesis, suggesting that the tumor-suppressive effects of Dnmt1 hypomorphic alleles may be mediated in part through reduced promoter hypermethylation. Our work is the first in vivo study to show the effects of reduced Dnmt levels on pancreatic tumor development.
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PMID:Reduction of pancreatic acinar cell tumor multiplicity in Dnmt1 hypomorphic mice. 2136 28

To investigate the changes in the levels of DNA methylation in the testis during development after neonatal transient exposure to DNA methyltransferase (DNMT) inhibitors, we orally administered Sprague-Dawley (SD) rats with 5-aza-2'-deoxycytidine (5-aza-CdR; 0.025 or 0.25 mg kg(-1)) or cadmium (Cd; 1, 2 or 4 mg kg(-1)) daily from days 3-7 postpartum (pp). Sperm numbers decreased at day 70 pp in all exposure groups. We then used a PCR-based assay, combined bisulfite restriction analysis (COBRA) and pyrosequencing to determine the degrees of DNA methylation. Both 5-aza-CdR and Cd reduced DNMT activity in vivo after 5 days' exposure at day 8 pp but not at day 70 pp. In contrast, the DNA methylation level of LINE-1 was not changed in the testis, either at day 8 pp or at day 70 pp. We observed increased apoptosis and an increase in the p53 mRNA level, accompanied by a decreased DNA methylation level in the p53 gene promoter region, at day 8 pp in testis for the 5-aza-CdR-exposed groups but not in the Cd-exposed group. The Cd-exposed group exhibited a degradation of seminiferous tubules and inhibition of a stepwise change in methylation in the coding region of c-fos in testis at day 70 pp. Because we observed toxic phenotype development accompanied by aberrant DNA methylation, DNA methylation may play a role in chemical induced testis damage, with different DNMT inhibitors affecting DNA methylation levels in gene- or stage-specific manner.
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PMID:Changes in the levels of DNA methylation in testis and liver of SD rats neonatally exposed to 5-aza-2'-deoxycytidine and cadmium. 2144 42

DNA methyltransferase (DNMT)-inhibiting nucleoside analogs reactivate the expression of tumor suppressor genes and apoptosis-related genes silenced by methylation, thus favoring the induction of apoptosis in tumor cells. Moreover, induction of DNA damage seems to contribute to their antitumor effect. However, the apoptotic signaling pathway induced by these demethylating drugs is not well understood. Here, we have investigated the induction of apoptosis by two nucleoside DNMT inhibitors, decitabine and zebularine, in leukemic T cells. Both inhibitors induced caspase-dependent apoptosis in Jurkat, CEM-6 and MOLT-4 leukemia T cell lines, all with mutant p53, whereas resting and activated normal T lymphocytes were highly resistant to these demethylating agents. Although decitabine and zebularine showed different ability to induce apoptosis and cell cycle arrest among the three cell lines, they similarly activated the intrinsic apoptotic pathway by inducing mitochondrial alterations such as Bak activation, loss of transmembrane potential and generation of reactive oxygen species (ROS). Accordingly, Bcl-2- and Bcl-x(L) -overexpressing Jurkat cells, as well as caspase-9-deficient Jurkat cells, were resistant to apoptosis induced by decitabine and zebularine. Interestingly, ROS production seemed to be necessary for the induction of apoptosis. Apoptotic events, such as Bak and caspase activation, started as soon as 20 hr after treatment with either decitabine or zebularine. In addition, progression of apoptosis triggered by both DNMT inhibitors was paralleled by the induction of DNA damage. Our results suggest that the mitochondrial apoptotic pathway activated by decitabine and zebularine in p53 mutant leukemic T cells depends mainly on the induction of DNA damage.
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PMID:The DNA methyltransferase inhibitors zebularine and decitabine induce mitochondria-mediated apoptosis and DNA damage in p53 mutant leukemic T cells. 2145 89

The mechanisms underlying the progression of noninvasive serous borderline ovarian tumors (SBOT) to low-grade invasive carcinomas are poorly understood. We recently showed that inhibition of p53 induces SBOT invasion by activating the PI3K/Akt pathway and transcriptionally repressing E-cadherin. In human cancers, aberrant DNA methylation is a common phenomenon, and it is thought to be involved in the progression from noninvasive to invasive ovarian carcinomas. In this study, we tested the hypothesis that inhibition of p53 downregulates E-cadherin by regulating the methylation of its promoter in SBOT cells. Here, we show that DNA methyltransferase-1 (DNMT1), but not DNMT3a or DNMT3b, was increased in SV40 LT-infected SBOT4 cells, SBOT4-LT and the low-grade invasive serous ovarian carcinoma-derived cell line MPSC1. Treatment with 5-Aza-dC, a DNMT1 inhibitor, restored E-cadherin promoter methylation and expression, and inhibited cell invasion in both invasive SBOT4-LT and MPSC1 cells. Moreover, knockdown of endogenous p53 using siRNA in SBOT3.1 cells induced DNMT1 expression and led to an increase in E-cadherin promoter methylation. Additionally, activation of the PI3K/Akt pathway is required for p53 inhibition-induced DNMT1 expression. The increase in DNMT1 was associated with the inhibition of p53-induced downregulation of E-cadherin and cell invasion. Our findings show an important role for p53 in the progression of SBOT to an invasive carcinoma, and suggest that downregulation of E-cadherin by DNMT1-mediated promoter methylation contributes to this process.
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PMID:Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells. 2147 13


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