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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cattle
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Cell Line
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DNA-Binding Proteins / genetics
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Endothelial Growth Factors / genetics
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects
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Genes, Tumor Suppressor* / drug effects
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Genes, p53 / drug effects
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Histone Deacetylase Inhibitors
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Histone Deacetylases / physiology*
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Humans
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Hydroxamic Acids / pharmacology
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Hypoxia / genetics
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Hypoxia / pathology
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lymphokines / genetics
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Male
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Mice
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Mice, Inbred C57BL
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / genetics*
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Nuclear Proteins / genetics
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Transcription Factors*
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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von Hippel-Lindau Disease / genetics
Substances
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DNA-Binding Proteins
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Endothelial Growth Factors
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Enzyme Inhibitors
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HIF1A protein, human
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Hif1a protein, mouse
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lymphokines
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Nuclear Proteins
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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trichostatin A
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Histone Deacetylases