title: Suberoylanilide hydroxamic Acid, a histone deacetylase inhibitor, alters multiple signaling pathways in hepatocellular carcinoma cell lines.
abstract: BACKGROUND
  Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has preclinical efficacy in hepatocellular carcinoma (HCC), despite an unclear molecular mechanism. We sought to further investigate the effects of SAHA on HCC. We hypothesize SAHA will inhibit HCC cellular proliferation through apoptosis and aid in further profiling SAHA's effect on HCC oncogenic pathways.
  
  
  METHODS
  HCC cell lines were treated with various concentrations of SAHA. Cell proliferation was determined by MTT and colonogenic assays. Cell lysates were analyzed via Western blotting for apoptotic and oncogenic pathway markers. Caspase glo-3/7 was used to assess apoptosis.
  
  
  RESULTS
  SAHA treatment demonstrated significant (<0.05) reduction in cell growth and colony formation through apoptosis and cell cycle arrest. Western analysis showed reduction in Notch, pAKT and pERK1/2 proteins. Interestingly, phosphorylated STAT3 was increased in all cell lines.
  
  
  CONCLUSIONS
  SAHA inhibits Notch, AKT, and Raf-1 pathways but not the STAT3 pathway. We believe that STAT3 may lead to cancer cell progression, reducing SAHA efficacy in HCC. Therefore, combination of SAHA and STAT or Notch inhibition may be a strategy for HCC treatment.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Selvi
authors.initials: S
authors.lastname: Kunnimalaiyaan
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Sokolowski
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: tcgamblin@mcw.edu.
authors.forename: T Clark
authors.initials: TC
authors.lastname: Gamblin
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: mkunnima@mcw.edu.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Kunnimalaiyaan
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; 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 / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020033:Protein Isoforms; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077337:Vorinostat; D051058:Oncogene Protein v-akt; D053148:Caspase 3; D053179:Caspase 7
keywords: AKT; Apoptosis; Hepatocellular carcinoma; Histone deacetylase inhibitor; Notch; Raf-1; SAHA; STAT3; Vorinostat