title: Histone deacetylase inhibitors downregulate checkpoint kinase 1 expression to induce cell death in non-small cell lung cancer cells.
abstract: BACKGROUND
  Histone deacetylase inhibitors (HDACis) are promising anticancer drugs; however, the molecular mechanisms leading to HDACi-induced cell death have not been well understood and no clear mechanism of resistance has been elucidated to explain limited efficacy of HDACis in clinical trials.
  
  
  RESULTS
  Here, we show that protein levels of checkpoint kinase 1 (Chk1), which has a major role in G(2) cell cycle checkpoint regulation, was markedly reduced at the protein and transcriptional levels in lung cancer cells treated with pan-and selective HDACis LBH589, scriptaid, valproic acid, apicidin, and MS-275. In HDACi treated cells Chk1 function was impaired as determined by decreased inhibitory phosphorylation of cdc25c and its downstream target cdc2 and increased expression of cdc25A and phosphorylated histone H3, a marker of mitotic entry. In time course experiments, Chk1 downregulation occurred after HDACi treatment, preceding apoptosis. Ectopic expression of Chk1 overcame HDACi-induced cell death, and pretreating cells with the cdc2 inhibitor purvalanol A blocked entry into mitosis and prevented cell death by HDACis. Finally, pharmacological inhibition of Chk1 showed strong synergistic effect with LBH589 in lung cancer cells.
  
  
  CONCLUSIONS
  These results define a pathway through which Chk1 inhibition can mediate HDACi-induced mitotic entry and cell death and suggest that Chk1 could be an early pharmacodynamic marker to assess HDACi efficacy in clinical samples.
authors.affiliation: Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Brazelle
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Kreahling
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gemmer
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ma
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Cress
authors.forename: Eric
authors.initials: E
authors.lastname: Haura
authors.forename: Soner
authors.initials: S
authors.lastname: Altiok
mesh_terms: D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D000071877:Checkpoint Kinase 1; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles; D008175:Lung Neoplasms / Q000201:enzymology*; D000077767:Panobinostat; D010766:Phosphorylation; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D011687:Purines / Q000494:pharmacology; D000099186:Histone Deacetylase 3
chemical_list: D000071877:Checkpoint Kinase 1; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D011494:Protein Kinases; D011687:Purines; D000099186:Histone Deacetylase 3; C471843:6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine; C000605867:CHEK1 protein, human; C110550:HDAC1 protein, human