Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes.
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.
Department of Molecular Biology, Pusan National University, Pusan, Korea.
M S
MS
Kim
H J
HJ
Kwon
Y M
YM
Lee
J H
JH
Baek
J E
JE
Jang
S W
SW
Lee
E J
EJ
Moon
H S
HS
Kim
S K
SK
Lee
H Y
HY
Chung
C W
CW
Kim
K W
KW
Kim
D000818:Animals; D002417:Cattle; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D016228:Endothelial Growth Factors / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D000860:Hypoxia / Q000235:genetics / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D006623:von Hippel-Lindau Disease / Q000235:genetics
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C012589:trichostatin A; D006655:Histone Deacetylases