p53-independent induction of Gadd45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 and NF-Y

Oncogene. 2003 Oct 30;22(49):7762-73. doi: 10.1038/sj.onc.1207091.

Abstract

Histone deacetylase (HDAC) inhibitors cause growth arrest at the G1 and/or G2/M phases, and induce differentiation and/or apoptosis in a wide variety of tumour cells. The growth arrest at G1 phase by HDAC inhibitors is thought to be highly dependent on the upregulation of p21/WAF1, but the precise mechanism by which HDAC inhibitors cause G2/M arrest or apoptosis in tumour cells is unknown. Gadd45 causes cell cycle arrest at the G2/M phase transition and participates in genotoxic stress-induced apoptosis. We show here that it is also induced by a typical HDAC inhibitor, trichostatin A (TSA), through its promoter, in a p53-independent manner. To identify the mechanism of activation of the gadd45 promoter, we performed luciferase reporter analyses and electrophoretic mobility shift assays. These revealed that both the Oct-1 and CCAAT sites are needed for the full activation by TSA. We also found that the transcription factors Oct-1 and NF-Y specifically bind to each site. Thus, HDAC inhibitors can induce Gadd45 through its promoter without the need for functional p53, and both the Oct-1 and NF-Y concertedly participate in TSA-induced activation of the gadd45 promoter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • CCAAT-Binding Factor / physiology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • DNA-Binding Proteins / physiology*
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation
  • Histone Deacetylase Inhibitors*
  • Host Cell Factor C1
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Intracellular Signaling Peptides and Proteins
  • Molecular Sequence Data
  • Octamer Transcription Factor-1
  • Osteosarcoma / pathology
  • Promoter Regions, Genetic
  • Protein Biosynthesis
  • Proteins / genetics*
  • Transcription Factors / physiology*
  • Tumor Suppressor Protein p53 / physiology*

Substances

  • CCAAT-Binding Factor
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • GADD45 protein
  • HCFC1 protein, human
  • Histone Deacetylase Inhibitors
  • Host Cell Factor C1
  • Hydroxamic Acids
  • Intracellular Signaling Peptides and Proteins
  • Octamer Transcription Factor-1
  • POU2F1 protein, human
  • Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • trichostatin A