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Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes

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.

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Figure 1: Activity and expression of HDAC are regulated by oxygen tension.
Figure 2: Effect of TSA on the regulation of p53, VHL, HIF-1α and VEGF expression.
Figure 3: Anti-angiogenic activity of TSA.
Figure 4: Regulation of hypoxia-responsible genes by HDAC overexpression.
Figure 5: Angiogenic stimulation of wt-HDAC1 overexpression.
Figure 6: Induction of HDAC in hypoxic tumor regions and inhibition of hypoxia-induced angiogenesis by TSA in Lewis lung carcinoma model.

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Acknowledgements

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.).

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Correspondence to Kyu-Won Kim.

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Kim, M., Kwon, H., Lee, Y. et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7, 437–443 (2001). https://doi.org/10.1038/86507

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