Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha.
Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha.
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发表时间：
2006
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通讯作者：
Donna M. Fath;Xianguo Kong;Dongming Liang;Zhao Lin;Andrew Chou;Yubao Jiang;Jie Fang;J. Caro;N. Sang
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作者：
Donna M. Fath;Xianguo Kong;Dongming Liang;Zhao Lin;Andrew Chou;Yubao Jiang;Jie Fang;J. Caro;N. Sang
低氧诱导因子（Hypoxia-inducible factors，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。使用组合的药理学，生物化学和遗传学方法，在这里，我们表明HDAI抑制HIF-α CAD的反式激活潜力。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在体内诱导p300的过度乙酰化并抑制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，是易于乙酰化。综上所述，我们的数据表明，脱乙酰酶活性是HIF-α CAD的反式激活潜力所不可或缺的，并支持乙酰化通过靶向HIF-α.p300复合物而不是通过直接乙酰化HIF-α来调节HIF功能的模型。HDAI抑制HIF-1 α和HIF-2 α转录激活潜能的证明独立于von Hippel-Lindau肿瘤抑制因子和p53功能，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-alphaCAD). 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-alphaCAD. 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-1alpha.p300 complex in vivo. In vitro acetylation analysis reveals that the p300CH1 region, but not HIF-alphaCAD, is susceptible to acetylation. Taken together, our data demonstrate that a deacetylase activity is indispensable for the transactivation potential of HIF-alphaCAD 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-1alpha and HIF-2alpha 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.