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Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes

Nature Medicine volume 7, pages 437–443 (2001)Cite this article

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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Authors and Affiliations

  1. Department of Molecular Biology, Pusan National University, Pusan, Korea

    Myoung Sook Kim, You Mie Lee, Jin Hyen Baek, Jae-Eun Jang, Sae-Won Lee, Eun-Joung Moon, Hae-Sun Kim & Seok-Ki Lee

  2. Department of Pharmacy, Pusan National University, Pusan, Korea

    Hae Young Chung

  3. Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea

    Ho Jeong Kwon

  4. Department of Pathology, College of Medicine, Seoul National University, Seoul, Korea

    Chul Woo Kim

  5. Angiogenesis Research Laboratory, College of Pharmacy, Seoul National University, Seoul, Korea

    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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