Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes

Nat Med. 2001 Apr;7(4):437-43. doi: 10.1038/86507.

Abstract

Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wild-type HDAC1 downregulated expression of p53 and von Hippel-Lindau tumor suppressor genes and stimulated angiogenesis of human endothelial cells. A specific HDAC inhibitor, trichostatin A (TSA), upregulated p53 and von Hippel-Lindau expression and downregulated hypoxia-inducible factor-1alpha and vascular endothelial growth factor. TSA also blocked angiogenesis in vitro and in vivo. TSA specifically inhibited hypoxia-induced angiogenesis in the Lewis lung carcinoma model. These results indicate that hypoxia enhances HDAC function and that HDAC is closely involved in angiogenesis through suppression of hypoxia-responsive tumor suppressor genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Cell Line
  • DNA-Binding Proteins / genetics
  • Endothelial Growth Factors / genetics
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Genes, Tumor Suppressor* / drug effects
  • Genes, p53 / drug effects
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases / physiology*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Hypoxia / genetics
  • Hypoxia / pathology
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / genetics*
  • Nuclear Proteins / genetics
  • Transcription Factors*
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • von Hippel-Lindau Disease / genetics

Substances

  • DNA-Binding Proteins
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines
  • Nuclear Proteins
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • trichostatin A
  • Histone Deacetylases