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Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins,

C-Y Gui1, L Ngo, W S Xu

  • 1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 22, 2004
PubMed

Insights

Histone deacetylase inhibitors like SAHA selectively activate cancer-fighting genes, such as p21(WAF1), by altering chromatin structure and protein binding at specific gene promoters.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Pharmacology

Background:

  • Histone deacetylase inhibitors (HDACi) show promise in cancer treatment by inducing cell growth arrest and apoptosis.
  • SAHA (Suberoylanilide hydroxamic acid) is an HDACi with demonstrated anticancer activity in clinical trials.
  • HDACi affect gene expression selectively, despite HDACs' widespread presence in chromatin.

Purpose of the Study:

  • To investigate the molecular mechanisms behind SAHA-induced gene activation at the p21(WAF1) promoter in ARP-1 cells.
  • To understand why SAHA selectively alters the expression of specific genes like p21(WAF1) but not others (e.g., p27(KIPI)).

Main Methods:

  • Analysis of histone modifications (acetylation, methylation) and chromatin accessibility (DNase I sensitivity) at the p21(WAF1) promoter.
  • Chromatin immunoprecipitation to assess the binding of HDAC1, Myc, and RNA polymerase II to the p21(WAF1) promoter.
  • Comparison of these changes with those at the p27(KIPI) and epsilon-globin gene promoters.

Main Results:

  • SAHA rapidly induced histone acetylation and methylation, alongside increased DNase I sensitivity and restriction enzyme accessibility at the p21(WAF1) promoter.
  • These epigenetic changes were specific to the p21(WAF1) promoter and not observed at the p27(KIPI) or epsilon-globin gene loci.
  • SAHA treatment led to decreased binding of HDAC1 and Myc, and increased binding of RNA polymerase II to the p21(WAF1) promoter.

Conclusions:

  • SAHA selectively alters chromatin structure and protein recruitment at target gene promoters, contributing to its gene-specific effects.
  • These findings provide mechanistic insights into how HDAC inhibitors like SAHA selectively modulate gene expression for anticancer effects.
  • The study highlights the importance of promoter-specific epigenetic changes in mediating the therapeutic actions of HDAC inhibitors.

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