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Assays for Validating Histone Acetyltransferase Inhibitors
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Histone deacetylase inhibitors: signalling towards p21cip1/waf1

Matthias Ocker1, Regine Schneider-Stock

  • 1Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany. Matthias.ocker@med1.imed.uni-erlangen.de

The International Journal of Biochemistry & Cell Biology
|April 7, 2007
PubMed

Insights

Histone deacetylase (HDAC) inhibitors combat cancer by increasing p21 expression, a key cell cycle regulator. This mechanism, involving histone acetylation and Sp1 sites, determines therapeutic success by influencing cell cycle arrest or apoptosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Chromatin-modifying enzymes, specifically histone deacetylases (HDAC), are crucial for maintaining a closed chromatin structure, leading to transcriptional repression.
  • Aberrant HDAC activity is frequently observed in human cancers, highlighting HDACs as significant targets for novel therapeutic strategies.
  • HDAC inhibitors represent a promising anti-cancer therapeutic approach.

Purpose of the Study:

  • To investigate the molecular mechanisms by which HDAC inhibitors activate the expression of the cyclin-dependent kinase inhibitor p21(cip1/waf1).
  • To explore the role of histone acetylation and Sp1 sites in the promoter region of p21(cip1/waf1) in response to HDAC inhibition.
  • To understand how p21(cip1/waf1) regulation influences therapeutic outcomes in cancer treatment.

Main Methods:

  • Analysis of histone acetylation patterns around the p21(cip1/waf1) promoter.
  • Investigation of Sp1 binding to the p21(cip1/waf1) promoter and the release of repressor HDAC1.
  • Assessment of p21(cip1/waf1) expression levels in response to HDAC inhibitor treatment.
  • Evaluation of p53-dependent and p53-independent regulatory pathways of p21(cip1/waf1).

Main Results:

  • HDAC inhibitors significantly enhance histone acetylation in the vicinity of the p21(cip1/waf1) promoter.
  • HDAC inhibitors promote the release of the repressor HDAC1 from Sp1 binding sites on the p21(cip1/waf1) promoter.
  • Up-regulation of p21(cip1/waf1) expression is observed through both p53-dependent and p53-independent mechanisms.

Conclusions:

  • HDAC inhibition activates p21(cip1/waf1) expression via epigenetic modifications and transcription factor modulation.
  • The therapeutic efficacy of HDAC inhibitors is contingent upon whether p21(cip1/waf1) up-regulation leads to cell cycle arrest or apoptosis.
  • Targeting HDACs offers a viable strategy for cancer therapy by modulating key cell cycle regulators.

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