title: Inhibition of Plk1 and Cyclin B1 expression results in panobinostat-induced G₂ delay and mitotic defects.
abstract: The development of clinically useful histone deacetylase inhibitors has expanded greatly. In a preclinical study, we showed that panobinostat (LBH589) inhibits cell cycle progression of human head and neck squamous cell carcinoma (HNSCC) cell lines at G₂/M and an associated decrease in expression of particular genes required for passage through G₂ and mitosis. In this study we sought to analyse the mechanistic underpinnings of panobinostat-induced growth arrest. HNSCC cell lines were synchronised and progression through mitosis monitored. We demonstrate that panobinostat causes a marked G₂ delay and mitotic defects. A loss of G₂-specific Plk1 and Cyclin B1 expression and co-incident increase in p21(Waf1/Cip1) expression is also shown. Furthermore, we show a significant loss of E2F1 recruitment to the promoters of these genes in response to panobinostat treatment. These data provide mechanistic evidence of panobinostat-induced cell cycle arrest and highlight its potential as a chemotherapeutic agent for HNSCC.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine and Montefiore Medical Center, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Prystowsky
authors.forename: Katherine
authors.initials: K
authors.lastname: Feeney
authors.forename: Nicole
authors.initials: N
authors.lastname: Kawachi
authors.forename: Cristina
authors.initials: C
authors.lastname: Montagna
authors.forename: Michelle
authors.initials: M
authors.lastname: Willmott
authors.forename: Christopher
authors.initials: C
authors.lastname: Wasson
authors.forename: Maciej
authors.initials: M
authors.lastname: Antkowiak
authors.forename: Olivier
authors.initials: O
authors.lastname: Loudig
authors.forename: Joanna
authors.initials: J
authors.lastname: Parish
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056744:Cyclin B1 / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects* / Q000235:genetics*; D000077767:Panobinostat; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000077195:Squamous Cell Carcinoma of Head and Neck; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1
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