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)

Increased risk for the development of endometrial cancer has been associated with unopposed oestrogen exposure, hyperoestrogenic factors, and a history of breast cancer treated long-term with tamoxifen (Tam). Stromal cell-derived factor-1, currently named as CXCL12, is a chemokine that, via binding to CXCR4 receptor, activates several downstream effectors and signalling pathways responsible for proliferation, survival, and migration of cancer cells. We observed that 17beta-estradiol (E2) and tamoxifen (Tam) increase the expression of CXCR4 and CXCL12 transcripts and proteins in oestrogen receptor positive (ER(+)) but not in negative (ER(-)02) Ishikawa endometrial adenocarcinoma (ISH) cell lines. However, the demethylating agent 5-Aza-2'-deoxycytidine profoundly elevated CXCR4 and CXCL12 expression in both ER(+) and ER(-)02 ISH cells. Bisulfite sequencing revealed that E2 and Tam up-regulate expression via demethylation of cytosine in the cytosine-guanosine dinucleotide island of CXCR4 and CXCL12 promoters. We also found that E2 and Tam significantly increased, for several hours, the expression of DNA methyltransferase 3B4 enzymatically inactive splice variant in ER(+) but not in ER(-)02 ISH cells. Our results suggest that E2 and Tam, through their ability for gene-transcription regulation, change the cellular milieu that maintains the hypermethylated stage of CpG islands of CXCR4 and CXCL12 promoters.
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PMID:Epigenetic up-regulation of CXCR4 and CXCL12 expression by 17 beta-estradiol and tamoxifen is associated with formation of DNA methyltransferase 3B4 splice variant in Ishikawa endometrial adenocarcinoma cells. 1736 37

The aim of this study was to estimate the relationship of endothelial dysfunction induced by intracellular S-adenosylhomocysteine (SAH) accumulation and DNA methylation in human umbilical vein endothelial cells (HUVEC). The isolated HUVEC were incubated with 3-deazaadenosine (DZA) to induce experimental intracellular SAH accumulation. The impairment of HUVEC function was assessed by changes in morphology and proliferative ability. The expression of DNA methyltransferase-1 (DNMT1) and the atherosclerosis related genes [oestrogen receptor-alpha (ER-alpha), extracellular superoxide dismutase (EC-SOD) and monocyte chemoattractant protein-1 (MCP-1)] were analysed using quantitative real-time PCR. Global DNA methylated status was measured using the cytosine extension assay. The methylated patterns of ER-alpha, EC-SOD and MCP-1 genes were determined with methylation-specific PCR. We found that DZA administration increased intracellular SAH levels progressively and simultaneously decreased Hcy content in medium. Moreover, the supplementation induced HUVEC apoptosis, inhibited proliferation ability and DNMT1 mRNA expression (P < 0.05) and furthermore reduced global DNA methylation status (P < 0.05). Correlation analysis showed the presence of a negative correlation between intracellular SAH concentration, proliferative ability, and expression of ER-alpha, EC-SOD, and DNMT1 (r = -0.89, -0.86, -0.92 and -0.88 respectively, P < 0.001); and a positive correlation with MCP-1 expression and DNA [(3)H]-dCTP incorporation (r = 0.89 and 0.93 respectively, P < 0.001). Our results showed that endothelial dysfunction induced by intracellular SAH accumulation is mediated by regulating the expression of atherosclerosis related genes in HUVEC, which is not related with gene promoter methylated patterns, but may be associated with altered global DNA hypomethylated status. These findings suggest that SAH can act as the potential molecular biological marker in the promotion of atherogenesis.
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PMID:Relationship of impairment induced by intracellular S-adenosylhomocysteine accumulation with DNA methylation in human umbilical vein endothelial cells treated with 3-deazaadenosine. 1995