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-1α 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.
| Original language | English |
|---|---|
| Pages (from-to) | 437-443 |
| Number of pages | 7 |
| Journal | Nature Medicine |
| Volume | 7 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2001 |
Bibliographical note
Funding Information:Acknowledgments We thank S.L. Schreiber for the gift of pBJ5-wt-HDAC1–expressing vector; J.A. Raleigh for hypoxia marker, pimonidazole and its associated antibody; and B.P. Yu for critical reading of the manuscript. Financial support was from the National Research Laboratory Fund (2000-N-NL-01-C-015), the Ministry of Science and Technology, Korea (to K-W.K.) and the Korea Science and Engineering Foundation (to H.J.K.).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)