Histone deacetylase inhibitors downregulate checkpoint kinase 1 expression to induce cell death in non-small cell lung cancer cells

PLoS One. 2010 Dec 14;5(12):e14335. doi: 10.1371/journal.pone.0014335.


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.

Methods and findings: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Carcinoma, Non-Small-Cell Lung / enzymology*
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Checkpoint Kinase 1
  • Down-Regulation
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / chemistry
  • Humans
  • Hydroxamic Acids / pharmacology
  • Indoles
  • Lung Neoplasms / enzymology*
  • Panobinostat
  • Phosphorylation
  • Protein Kinases / biosynthesis*
  • Protein Kinases / genetics
  • Purines / pharmacology


  • 6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Purines
  • Panobinostat
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases
  • histone deacetylase 3