Nature Medicine
7, 437 - 443 (2001)
doi:10.1038/86507
Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genesMyoung Sook Kim1, Ho Jeong Kwon3, You Mie Lee1, Jin Hyen Baek1, Jae-Eun Jang1, Sae-Won Lee1, Eun-Joung Moon1, Hae-Sun Kim1, Seok-Ki Lee1, Hae Young Chung2, Chul Woo Kim4
& Kyu-Won Kim51
Department of Molecular Biology, Pusan National University, Pusan, Korea
2
Department of Pharmacy, Pusan National University, Pusan, Korea
3
Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea
4
Department of Pathology, College of Medicine, Seoul National University, Seoul, Korea. 5
Angiogenesis Research Laboratory, College of Pharmacy, Seoul National University, Seoul, Korea.
Correspondence should be addressed to Kyu-Won Kim qwonkim@plaza.snu.ac.krLow 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-1 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.
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