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

• Published in: PloS one Vol. 5; no. 12; p. e14335
• Main Authors: Brazelle, William, Kreahling, Jenny M, Gemmer, Jennifer, Ma, Yihong, Cress, W Douglas, Haura, Eric, Altiok, Soner
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.12.2010; Public Library of Science (PLoS)
• Subjects: Antineoplastic drugs; Antitumor agents; Apoptosis; Biochemistry; Biopsy; Cancer; Cancer cells; Cancer treatment; Carcinoma, Non-Small-Cell Lung - enzymology; Cdc2 protein; Cell Biology/Cell Growth and Division; Cell Biology/Cell Signaling; Cell Cycle; Cell death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Checkpoint Kinase 1; CHK1 protein; Chromatin; Clinical trials; Cytotoxicity; Deoxyribonucleic acid; DNA; Down-Regulation; Drug dosages; Drugs; Ectopic expression; Enzymes; Gene expression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Heat shock proteins; Histone deacetylase; Histone Deacetylase 1 - antagonists & inhibitors; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - chemistry; Histone H3; Humans; Hydroxamic Acids - pharmacology; Indoles; Inhibition; Inhibitors; Kinases; Lung cancer; Lung diseases; Lung Neoplasms - enzymology; Medical research; Mitosis; Molecular modelling; Mortality; Non-small cell lung cancer; Non-small cell lung carcinoma; Oncology; Oncology/Lung Cancer; Pancreatic cancer; Pharmacodynamics; Pharmacology; Pharmacology/Personalized Medicine; Phosphorylation; Protein Kinases - biosynthesis; Protein Kinases - genetics; Purines - pharmacology; Synergistic effect; Transcription; Valproic acid; Florida; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0014335

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. 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. 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.