title: Inhibition of DNA methyltransferases, histone deacetylases and lysine-specific demethylase-1 suppresses the tumorigenicity of the ovarian cancer ascites cell line SKOV3.
abstract: Ovarian cancer is one of the most lethal female malignancies and epigenetic abnormalities are thought to play a vital role in the pathogenesis, development and progression of ovarian cancer. Our goal was to investigate whether the combination of trichostatin A (TSA) and 5-aza-2'-deoxycytidine (decitabine) was superior to single agent on tumorigenicity of ovarian cancer cells. We found that tumorigenicity and metastasis of SKOV3 cells were significantly suppressed by the combination of TSA and decitabine in xenograft mouse models. Migration capacity was markedly suppressed through the induction of E-cadherin and suppression of N-cadherin when treated with TSA and decitabine. Invasion was also suppressed at least partially through inhibition of MMP-2 and MMP-9 with the combined treatment. The combination drugs markedly inhibited spheroid formation and significantly impaired migration and invasion capacity of spheroid derived cells through inhibition of Twist, N-cadherin, MMP-2, MMP-9 and induction of E-cadherin. Epigenetically, the activity of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) were markedly inhibited when TSA was used in combination with decitabine, especially the expression of DNMT3A/3B and HDAC1/2. Acetylation of histone H3 and H4 were more markedly stimulated with the combination than with either agent alone. The expression level of lysine-specific demethylase-1 (LSD1) was also suppressed. The transcription activity marker dimethylated-H3K4 was induced, but the dimethylated-H3K9 was suppressed by exposure to the combined drugs. These results suggest that the combination of TSA and decitabine significantly suppresses tumorigenicity by inhibiting migration and invasion of ovarian cancer cells via regulating the expression of the cadherins and MMPs, which may be epigenetically regulated by DNA methylation and histone modification.
authors.affiliation: Division of Gynecologic Oncology, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: Fanliang
authors.initials: F
authors.lastname: Meng
authors.forename: Guiqin
authors.initials: G
authors.lastname: Sun
authors.forename: Mei
authors.initials: M
authors.lastname: Zhong
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Yu
authors.forename: Molly A
authors.initials: MA
authors.lastname: Brewer
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001201:Ascites; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015820:Cadherins / Q000096:biosynthesis / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology*; D018874:Spheroids, Cellular / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000037:antagonists & inhibitors
chemical_list: D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C012589:trichostatin A; D000077209:Decitabine; D056466:Histone Demethylases; C495195:KDM1A protein, human; D015254:DNA Modification Methylases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D006655:Histone Deacetylases; D001374:Azacitidine