title: Cytostatic and apoptotic effects of DNMT and HDAC inhibitors in endometrial cancer cells.
abstract: DNA methyltransferase (DNMT) and histone deacetylase are key enzymes mediating the epigenetic regulation of gene expression. DNA hypermethylation and/or histone deacetylation in promoter regions is often associated with downregulation or silencing of transcription. Epigenetic silencing of tumor suppressor genes plays an important role in malignant transformation. DNMT and HDAC inhibitors induce DNA demethylation and histone acetylation, respectively, leading to reactivation of silenced genes, and dramatic morphological and functional changes in cancer cells. In this study, we have conducted a series of experiments to characterize the effects of epigenetic inhibitors in endometrial cancer cells. Using cell lines representing different stages of endometrioid cancers, we examined the impact of DNMT inhibitor, ADC, and HDAC inhibitor, TSA, on cell cycle and apoptosis. We found that while both reagents were capable of inhibiting cell proliferation and inducing cell apoptosis, TSA appeared to be a more potent apoptosis inducer, but with a smaller effect on cell cycle. On the other hand, ADC exhibited strong effects on cell cycle regulation, but had smaller impact on cell apoptosis. We subsequently confirmed the presence of a strong synergism between DNMT and HDAC inhibitors. Thus, ADC and TSA exhibited strong cytostatic and apoptotic effects in endometrial cancer cell lines and the combined application may deliver the highest response in the clinical setting.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Xu
authors.forename: Juan
authors.initials: J
authors.lastname: Ren
authors.forename: Hai Bin
authors.initials: HB
authors.lastname: Chen
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
authors.forename: Qingyou
authors.initials: Q
authors.lastname: Liu
authors.forename: Run
authors.initials: R
authors.lastname: Zhang
authors.forename: Shi-Wen
authors.initials: SW
authors.lastname: Jiang
authors.affiliation: Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404- 3089. Jiang_s@mercer.edu.
authors.forename: Jinping
authors.initials: J
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D009367:Neoplasm Staging
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D004248:DNA (Cytosine-5-)-Methyltransferases; D006655:Histone Deacetylases; D001374:Azacitidine