Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes
Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes
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DOI：
10.1038/86507
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发表时间：
2001-04-01
期刊：
影响因子：
82.9
通讯作者：
Kim, KW
中科院分区：
文献类型：
--
作者：
Kim, MS;Kwon, HJ;Kim, KW
低氧张力通过增强血管生成影响肿瘤进展;组蛋白脱乙酰酶（HDAC）与染色质组装和肿瘤发生的改变有关。在这里，我们显示诱导缺氧下的HDAC和阐明的作用，HDAC在调节缺氧诱导的血管生成。过表达的野生型HDAC 1下调p53和von Hippel-Lindau肿瘤抑制基因的表达，并刺激人内皮细胞的血管生成。一种特异性HDAC抑制剂，阿司他丁A（TSA），上调p53和von Hippel-Lindau表达，下调缺氧诱导因子-1 α和血管内皮生长因子。TSA还在体外和体内阻断血管生成。TSA特异性抑制刘易斯肺癌模型中缺氧诱导的血管生成。这些结果表明，缺氧增强HDAC的功能，HDAC是密切参与血管生成，通过抑制缺氧反应的肿瘤抑制基因。
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-1 alpha 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.