title: Hypomethylation reduced the aggressive potential of human malignant mesothelioma cells.
abstract: Epigenetic modifications have been implicated in the development of therapeutic resistance responsible for the poor prognosis of human malignant mesothelioma (HMM). To find a potential way to overcome this therapeutic resistance, this study investigated the anticancer effects of a DNA demethylating agent, 5-Aza-2'-Deoxycytidine (5-aza-dC), on HMM cells. The 5-aza-dC exhibited minimal detrimental effects on cell survival. However, treatment with 5-aza-dC significantly altered the biological characteristics associated with malignancy, such as cell migration and cell interaction, colony-forming capacity, and invasiveness. Moreover, it significantly reduced the fraction of side population (SP) cells, which are reportedly enriched for more aggressive cells. Large-scale methylation analysis based on methylated DNA immunoprecipitation revealed a more than two fold increase in the methylation level of major tumor suppressor genes in the SP fraction. The data indicated that SP cells might acquire malignancy by hypermethylation of tumor suppressor genes. Treatment with 5-aza-dC could attack more malignant cells through the modification of their methylation status. The results indicate that the modulation of DNA methylation might be a valuable strategy to overcome the therapeutic resistance of HMM. Moreover, ensuing changes in the biological characteristics provide a basis for further analysis of the role of methylation in HMM carcinogenesis.
authors.affiliation: Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: N-Y
authors.initials: NY
authors.lastname: Kim
authors.affiliation: Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: M-C
authors.initials: MC
authors.lastname: Kim
authors.affiliation: Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D000077209:Decitabine; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology*; D000086002:Mesothelioma, Malignant
chemical_list: C000717967:DNMT3A protein, human; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D001374:Azacitidine