title: Antitumor activity of a novel histone deacetylase inhibitor (S)-HDAC42 in oral squamous cell carcinoma.
abstract: The aberrant regulation of epigenetic systems including histone acetylation contributes to inappropriate gene expression in cancer cells. In this study, we investigated the antitumor effects of the novel histone deacetylase inhibitor (S)-HDAC42 in oral squamous cell carcinoma (OSCC) cells. The antiproliferative effect of (S)-HDAC42 was multifold higher than that of suberoylanilide hydroxamic acid in a panel of oral squamous carcinoma cell lines examined. (S)-HDAC42 mediated caspase-dependent apoptosis by targeting multiple signaling pathways relevant to cell cycle progression and survival. We demonstrated that (S)-HDAC42 downregulated the levels of phospho-Akt, cyclin D1, and cyclin-dependent kinase 6, accompanied by increased p27 and p21 expression. In addition, (S)-HDAC42 suppressed NF-κB signaling by blocking tumor necrosis factor-α-induced nuclear translocation, and activated reactive oxygen species generation. Finally, (S)-HDAC42 exhibited high potency in suppressing OSCC tumor growth in a Ca922 xenograft nude mouse model. Together, these findings underscore the translational value of (S)-HDAC42 in fostering new therapeutic strategies for OSCC.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Bai
authors.forename: Chang-Fang
authors.initials: CF
authors.lastname: Chiu
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Sargeant
authors.forename: Tzong-Ming
authors.initials: TM
authors.lastname: Shieh
authors.forename: Ying-Chu
authors.initials: YC
authors.lastname: Wang
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Weng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy*; D016328:NF-kappa B / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077337:Vorinostat; D051057:Proto-Oncogene Proteins c-akt; D051361:Cyclin-Dependent Kinase 6