Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes

Myoung Sook Kim; Ho Jeong Kwon; You Mie Lee; Jin Hyen Baek; Jae Eun Jang; Sae Won Lee; Eun Joung Moon; Hae Sun Kim; Seok Ki Lee; Hae Young Chung; Chul Woo Kim; Kyu Won Kim

doi:10.1038/86507

Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes

Myoung Sook Kim, Ho Jeong Kwon, You Mie Lee, Jin Hyen Baek, Jae Eun Jang, Sae Won Lee, Eun Joung Moon, Hae Sun Kim, Seok Ki Lee, Hae Young Chung, Chul Woo Kim, Kyu Won Kim

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719 Scopus citations

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	https://doi.org/10.1038/86507
State	Published - 2001

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title = "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.",

author = "Kim, {Myoung Sook} and Kwon, {Ho Jeong} and Lee, {You Mie} and Baek, {Jin Hyen} and Jang, {Jae Eun} and Lee, {Sae Won} and Moon, {Eun Joung} and Kim, {Hae Sun} and Lee, {Seok Ki} and Chung, {Hae Young} and Kim, {Chul Woo} and Kim, {Kyu Won}",

year = "2001",

doi = "10.1038/86507",

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T1 - Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes

AU - Kim, Myoung Sook

AU - Kwon, Ho Jeong

AU - Lee, You Mie

AU - Baek, Jin Hyen

AU - Jang, Jae Eun

AU - Lee, Sae Won

AU - Moon, Eun Joung

AU - Kim, Hae Sun

AU - Lee, Seok Ki

AU - Chung, Hae Young

AU - Kim, Chul Woo

AU - Kim, Kyu Won

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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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Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes

Abstract

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