title: The HDAC inhibitor, panobinostat, induces apoptosis by suppressing the expresssion of specificity protein 1 in oral squamous cell carcinoma.
abstract: Inhibitors of histone deacetylases (HDACs) represent a novel class of therapeutic anticancer agents. Panobinostat (LBH589) induces apoptosis through the regulation of specificity protein 1 (Sp1) in the oral squamous cell carcinoma (OSCC) cell lines, HN22 and HSC4. In this study, we analyzed the underlying signaling pathways and the mechanisms involved in this process by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, 4',6-diamidino-2-phenylindole (DAPI) staining, immunocytochemistry and western blot analysis. LBH589 significantly reduced cell growth and the sub-G1 cell population and induced apoptosis. Sp1 protein expression was significantly reduced following treatment with LBH589 in a concentration-dependent manner. Furthermore, LBH589 upregulated the expression of p27 and p21 and downregulated the expression of cyclin D1, myeloid cell leukemia-1 (Mcl-1) and survivin; this led to the activation of apoptotic signaling pathways through the increase of Bax expression and the decrease of Bid and Bcl-xL expression. Treatment with LBH589 also induced the cleavage of caspase-3 and PARP in the HN22 and HSC4 cells. Taken together, our data demonstrate that LBH589 induces the apoptosis of OSCC cells by suppressing Sp1 expression, indicating that LBH589 may be a promising chemotherapeutic agent for the treatment of OSCC.
authors.affiliation: Department of Oral Pharmacology, School of Dentistry and Institute of Dental Bioscience, BK21 project, Chonbuk National University, Jeonju 651-756, Republic of Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Jeon
authors.forename: Seon Mi
authors.initials: SM
authors.lastname: Ko
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Cho
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Chae
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000473:pathology; D000077767:Panobinostat; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D016329:Sp1 Transcription Factor; D013778:Tetrazolium Salts; D013844:Thiazoles; C070380:3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; C007293:DAPI; D000077767:Panobinostat; D006655:Histone Deacetylases