Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-α
Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-α
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DOI：
10.1074/jbc.m600456200
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发表时间：
2006-05-12
影响因子：
4.8
通讯作者：
Sang, NL
中科院分区：
文献类型：
--
作者：
Fath, DM;Kong, XG;Sang, NL
缺氧诱导因子（hypoxia-induciblefactors，HIF）是一类调节氧供应、糖代谢和血管生成的异源二聚体转录因子. HIF功能需要通过HIF-α的C-末端反式激活结构域（HIF-α CAD）募集p300/CREB结合蛋白，这两种共激活因子具有组蛋白乙酰转移酶活性。组蛋白去乙酰化酶抑制剂（HDAI）诱导分化或凋亡，抑制肿瘤生长和血管生成，因此作为抗癌药物被广泛研究。通过结合药理学、生物化学和遗传学方法，我们发现HDAI抑制HIF-α CAD的转录激活潜力。这种抑制与肿瘤抑制因子von Hippel-Lindau或p53的功能或HIF-α的降解无关。我们还证明了低浓度的HDAI在肿瘤细胞中抑制HIF靶基因的充分性。我们进一步表明HDAI诱导p300的过度乙酰化，并在体内抑制HIF-1 α p300复合物。体外乙酰化分析表明，p300 CH 1区域，但不是HIF-α CAD，是易受乙酰化。总之，我们的数据表明，去乙酰化酶活性是必不可少的转录潜力的HIF-CAD和支持的模型，乙酰化调节HIF功能的靶向HIF-α p300复合物，而不是直接乙酰化HIF-α。HDAI抑制HIF-1 α和HIF-2 α的反式激活潜力，而与von Hippel-Lindau肿瘤抑制因子和p53功能无关，这一证明表明HDAI可能在除肿瘤外的广泛组织中具有生物学效应。
Hypoxia- inducible factors (HIFs) are heterodimeric transcription factors regulating the oxygen supply, glucose metabolism, and angiogenesis. HIF function requires the recruitment of p300/CREB-binding protein, two coactivators with histone acetyltransferase activity, by the C-terminal transactivation domain of HIF-alpha (HIF-alpha CAD). Histone deacetylase inhibitors (HDAIs) induce differentiation or apoptosis and repress tumor growth and angiogenesis, hence being explored intensively as anti-cancer agents. Using combined pharmacological, biochemical, and genetic approaches, here we show that HDAIs repress the transactivation potential of HIF-alpha CAD. This repression is independent of the function of tumor suppressors von Hippel-Lindau or p53 or the degradation of HIF-alpha. We also demonstrate the sufficiency of low concentrations of HDAIs in repression of HIF target genes in tumor cells. We further show that HDAIs induce hyperacetylation of p300 and repress the HIF-1 alpha p300 complex in vivo. In vitro acetylation analysis reveals that the p300CH1 region, but not HIF-alpha CAD, is susceptible to acetylation. Taken together, our data demonstrate that a deacetylase activity is indispensable for the transactivation potential of HIF-CAD and support a model that acetylation regulates HIF function by targeting HIF-alpha p300 complex, not by direct acetylating HIF-alpha. The demonstration that HDAIs repress both HIF-1 alpha and HIF-2 alpha transactivation potential independently of von Hippel-Lindau tumor suppressor and p53 function indicates that HDAIs may have biological effects in a broad range of tissues in addition to tumors.