Mechanism of Cell Cycle Arrest Caused by Histone Deacetylase Inhibitors in Human Carcinoma Cells

J Antibiot (Tokyo). 2000 Oct;53(10):1191-200. doi: 10.7164/antibiotics.53.1191.

Abstract

Inhibitors of histone deacetylase (HDAC) block cell cycle progression at G1 in many cell types. We investigated the mechanism by which trichostatin A (TSA), a specific inhibitor of HDAC, induces G1 arrest in human cervix carcinoma HeLa cells. TSA treatment induced histone hyperacetylation followed by growth arrest in G as well as hypophosphorylation of pRb. The Cdk4 kinase activity was essentially unchanged during the TSA-induced G1 arrest. On the other hand, the arrest was accompanied by down-regulation of kinase activity of Cdk2, although the total protein levels of Cdk2 and its activator Cdc25A were unaffected. Upon TSA treatment, amounts of cyclin E and the CDK inhibitor p21WAF1/Cip1 were markedly increased, while that of cyclin A was reduced. The induction of p21 and down-regulation of cyclin A correlated well with the decreased Cdk2 activity and cell cycle arrest. Furthermore, gel filtration chromatography showed the association of p21 with the cyclin E-Cdk2 complex, suggesting that the activation of Cdk2 by the enhanced expression of cyclin E is blocked by the increased p21. The elevated expression of p2 is also observed in cells treated with trapoxin and FR901228, structurally unrelated histone deacetylase inhibitors. A human colorectal carcinoma cell line lacking both alleles of the p21 gene (p21-/-) was resistant to TSA several times more than the parental line (p21+/+). These results suggest that the suppression of Cdk2 kinase activity due to p21 overexpression play a critical role in HDAC inhibitor-induced growth inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology*
  • CDC2-CDC28 Kinases*
  • Cell Division
  • Colorectal Neoplasms
  • Cyclin A / metabolism
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases / metabolism
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Female
  • G1 Phase / drug effects*
  • Gene Expression Regulation, Neoplastic
  • HeLa Cells
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured

Substances

  • Antibiotics, Antineoplastic
  • Cyclin A
  • Cyclin E
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • TCEAL1 protein, human
  • Transcription Factors
  • trichostatin A
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases