title: Trichostatin A and sirtinol suppressed survivin expression through AMPK and p38MAPK in HT29 colon cancer cells.
abstract: BACKGROUND
  Elevated levels of survivin and histone deacetylases (HDACs) are often found over-expressed in human cancers, including colorectal cancer, and have been implicated in tumorigenesis. HDAC inhibition induces growth arrest and cell death in various transformed cell; however, the mechanisms by which this reduces cell viability in colorectal cancer cells remain unexplained.
  
  
  METHODS
  We explored the actions of two HDAC inhibitors, trichostatin A (TSA) and sirtinol, in HT29 colon cancer cells.
  
  
  RESULTS
  TSA and sirtinol induced apoptosis and inhibited cell proliferation in HT29 cells. These results are associated with the modulation of survivin. Survivin promoter luciferase activity and Sp1, a transcription factor that contributes to survivin expression, were suppressed in cells exposed to TSA or sirtinol. TSA and sirtinol also activated p38 mitogen-activated protein kinase (p38MAPK) and AMP-activated protein kinase (AMPK). Inhibitors of p38MAPK or AMPK signaling abrogated TSA and sirtinol's effects of decreasing cell viability. Survivin promoter luciferase activity in the presence of TSA or sirtinol was restored by AMPK dominant negative mutant or p38MAPK inhibitor. Furthermore, Sp1 binding to the survivin promoter region decreased while p63 binding to the promoter region increased after TSA or sirtinol exposure.
  
  
  CONCLUSIONS
  We report a p38MAPK- and AMPK-mediated downregulation of survivin, and its functional correlation with decreased colon cancer cell viability in the presence of HDAC inhibitor. p63 and Sp1 may also contribute to TSA and sirtinol actions.
  
  
  CONCLUSIONS
  This study delineates, in part, the underlying mechanisms of TSA and sirtinol in decreasing survivin expression and subsequent colon cancer cell viability.
authors.affiliation: Division of General Surgery, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Ya-Fen
authors.initials: YF
authors.lastname: Hsu
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Lin
authors.forename: De-Shin
authors.initials: DS
authors.lastname: Yang
authors.forename: George
authors.initials: G
authors.lastname: Hsiao
authors.forename: George
authors.initials: G
authors.lastname: Ou
authors.forename: Pei-Ting
authors.initials: PT
authors.lastname: Chiu
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Huang
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Kuo
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D009284:Naphthols / Q000494:pharmacology*; D008926:Plicamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000378:metabolism; D000077022:Survivin; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; D001549:Benzamides; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D009284:Naphthols; D016329:Sp1 Transcription Factor; D000077022:Survivin; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C439060:sirtinol; C012589:trichostatin A; C066851:mithramycin A; D008156:Luciferases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D008926:Plicamycin