title: 5-Azacytidine regulates matrix metalloproteinase-9 expression, and the migration and invasion of human fibrosarcoma HT1080 cells via PI3-kinase and ERK1/2 pathways.
abstract: Abnormal methylation of promoter CpG islands is one of the hallmarks of cancer cells, and is catalyzed by DNA methyltransferases. 5-azacytidine (5-aza C), a methyltransferase inhibitor, can cause demethylation of promoter regions of diverse genes. Epigenetic processes contribute to the regulation of matrix metalloproteinase (MMP) expression. However, little is known about the mechanisms and effects of 5-aza C on the invasive and migratory capacities of human fibrosarcoma HT1080 cells. In the present study, we found that 5-aza C induces MMP-9 activity, as determined by zymography. HT1080 cell proliferation was determined following 5-aza C administration by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle was examined by flow cytometry. 5-aza C treatment inhibited cell proliferation without affecting cell viability. Furthermore, 5-aza C significantly promoted migration and invasion of HT1080 cells. 5-aza C treatment enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and phosphoinositide (PI)3-kinase/Akt, and their inhibitors blocked MMP-9 activity induction, and cellular invasion and migration. Together, these findings suggest that promoter methylation may be one of the mechanisms modulating MMP-9 levels in HT1080 cells, and that 5-aza C-induced MMP-9 production is associated with the activation of ERK and PI3-kinase/Akt signaling pathways.
authors: Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju 32588, Republic of Korea.
authors: Seon-Mi
authors: SM
authors: Yu
authors: Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju 32588, Republic of Korea.
authors: Song Ja
authors: SJ
authors: Kim
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001374:Azacitidine / Q000009:adverse effects*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000187:drug effects; D005354:Fibrosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D001374:Azacitidine