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Histone deacetylase inhibitors activate p21(WAF1) expression via ATM

Rong Ju1, Mark T Muller

  • 1Department of Molecular Genetics, The Ohio State University, Columbus, Ohio 43210, USA.

Cancer Research
|June 5, 2003
PubMed

Insights

Histone deacetylase inhibitors normally increase p21(WAF1) gene expression, but this is impaired in Ataxia telangiectasia (AT) cells. Restoring ATM function in AT cells fully recovers this gene induction, highlighting ATM's role in HDAC inhibitor response.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Histone deacetylase (HDAC) inhibitors are known to induce cell cycle arrest via p21(WAF1) gene expression.
  • Ataxia telangiectasia (AT) is a genetic disorder characterized by DNA repair defects.

Purpose of the Study:

  • To investigate the role of ATM in p21(WAF1) gene induction by HDAC inhibitors.
  • To explore the involvement of phosphatidylinositol 3'-kinase activity in this process.

Main Methods:

  • Comparing p21(WAF1) induction in AT cells versus wild-type (WT) cells treated with HDAC inhibitors (depsipeptide, trichostatin A).
  • Assessing the effect of ectopic WT ATM gene expression in AT cells.
  • Evaluating the impact of caffeine and wortmannin on p21(WAF1) induction.
  • Analyzing promoter activity of p21(WAF1), topoisomerase IIIalpha, and SV40.
  • Measuring H3 and H4 histone acetylation levels.

Main Results:

  • p21(WAF1) induction by HDAC inhibitors was defective in AT cells but normal in WT cells.
  • Ectopic expression of WT ATM restored p21(WAF1) induction in AT cells.
  • Phosphatidylinositol 3'-kinase activity, inhibited by caffeine and wortmannin, is essential for p21(WAF1) induction.
  • Activation of p21(WAF1), topoisomerase IIIalpha, and SV40 promoters by HDAC inhibitors was reduced in AT cells.
  • Histone acetylation levels were similar in AT and WT cells despite differential gene induction.

Conclusions:

  • ATM plays a crucial role in p21(WAF1) gene induction mediated by HDAC inhibitors.
  • The phosphatidylinositol 3'-kinase pathway is involved in this regulatory mechanism.
  • ATM is implicated in histone acetylation-mediated gene regulation beyond p21(WAF1).

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