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)

Epigenetic alterations such as histone acetylation and DNA methylation play an important role in the regulation of gene expression for cell cycles and apoptosis that may affect the chemosensitivity of cancers. Previously, we have reported that the combination of suberoylanilide hydroxamic acid (SAHA), a newly developed histone deacetylase inhibitor, with cisplatin (CDDP) possessed synergistic cytotoxicity against human oral squamous cell carcinoma (OSCC) cell line HSC-3. In this study, we used a novel DNA methyltransferase inhibitor, zebularine (Zeb), to investigate the epigenetic influence on the sensitivity of carcinoma cell lines to 5-fluorouracil (5-FU) or CDDP by evaluating apoptotic inducibility. Treatment with CDDP or 5-FU either alone or in combination with Zeb or SAHA continued for 48 or 72 h. In HSC-3 cells, Zeb had chemosensitive efficacy with CDDP, but not 5-FU, whereas SAHA showed efficacy with both CDDP and 5-FU. We showed that Zeb has strong anti-proliferative activity against HSC-3 cells, shown by decreased cellular growth and G2/M cell cycle phase accumulation. Furthermore, DNA methylation could be a regulatory mechanism for dihydropyrimidine dehydrogenase (DPD), known to be a principal factor in 5-FU resistance. CDHP (5-chloro-2,4-dihydroxypyridine), an inhibitor of DPD, had an enhancing effect on the apoptotic ability of 5-FU alone or 5-FU/Zeb combination. In conclusion, the present study suggests that low-dose (IC20) Zeb may sensitize cancer cells to CDDP, which may be an important characteristic for solid cancer treatment, and that DPD and other agents activated by Zeb in cancer cells could be an inhibitory factor in the response to apoptosis induced by 5-FU.
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PMID:Epigenetic regulation of chemosensitivity to 5-fluorouracil and cisplatin by zebularine in oral squamous cell carcinoma. 1798 71

Approximately 85% of a single administered dose of 5-fluorouracil (5-FU) will be degraded by dihydropyrimidine dehydrogenase (DYPD). Studies have highlighted a link between the complete or partial loss of DYPD function and clinical responses to 5-FU; however, the underlying molecular basis of DPD deficiency remains poorly understood. Hence, the aim of the present study was to evaluate the prevailing hypothesis which suggests that overexpression of LINC00261 possesses the ability to modulate the methylation-dependent repression of DPYD, ultimately resulting in an elevation of the sensitivity of human esophageal cancer cells to 5-FU. LINC00261 levels were initially quantified, followed by analysis of DYPD methylation within the cancerous tissues collected from 75 patients diagnosed with esophageal cancer undergoing 5-FU-based adjuvant chemotherapy. In an attempt to determine the levels of LINC00261 related to the esophageal cancer cell resistance to 5-FU and to identify the interaction between the levels of LINC00261 and methylation of the DYPD promoter, esophageal cancer cells TE-1 and -5 were prepared, in which LINC00261 and the 5-FU-resistant TE-1 and -5 cells were overexpressed. The levels of LINC00261 were reduced among the cancerous tissues obtained from patients exhibiting resistance to 5-FU. Overexpression of LINC00261 was determined to dramatically inhibit proliferation and resistance to apoptosis among 5-FU-resistant TE-1 and -5 cells, whereas silencing of LINC00261 was determined to enhance proliferation and resistance to apoptosis among the TE-1 and -5 cells. DPYD, a confirmed target of LINC00261, displayed a greater incidence of DNA methylation among patient's sensitive to 5-FU. A key finding revealed that overexpressed LINC00261 could increase the methylation of the DPYD promoter through the recruitment of DNA methyltransferase (DNMT), which, in turn, acts to decrease DPYD activity in 5-FU-resistant TE-1 cells, whereas a reversible change was recorded once the demethylation reagent 5-aza-2'-deoxyctidine was employed to treat the 5-FU-resistant TE-1 cells. Taken together, the results of the study provided evidence emphasizing the distinct antitumor ability of LINC00261 in cases of esophageal cancer, which was manifested by overexpression of LINC00261 detected to increase the sensitivity of human esophageal cancer cells to 5-FU by mediating methylation-dependent repression of DPYD. Our study highlighted the potential of LINC00261 as a novel target capable of improving the chemotherapeutic response and survival of patients with esophageal cancer.-Lin, K., Jiang, H., Zhuang, S.-S., Qin, Y.-S., Qiu, G.-D., She, Y.-Q., Zheng, J.-T., Chen, C., Fang, L., Zhang, S.-Y. Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer.
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PMID:Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer. 3022 8