Coordinated Action of Hypoxia-inducible Factor-1α and β-Catenin in Androgen Receptor Signaling
Coordinated Action of Hypoxia-inducible Factor-1α and β-Catenin in Androgen Receptor Signaling
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DOI：
10.1074/jbc.m112.388298
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发表时间：
2012-09-28
影响因子：
4.8
通讯作者：
Yamaji, Ryoichi
中科院分区：
文献类型：
--
作者：
Mitani, Takakazu;Harada, Naoki;Yamaji, Ryoichi
雄激素受体（AR）作为一种配体依赖性转录因子，在雄激素依赖性和去势抵抗性前列腺癌的发生和发展中起着关键作用。去势导致前列腺癌细胞缺氧，缺氧通过低氧诱导因子（HIF）-1 α在模拟去势抵抗阶段的低血清雄激素水平下增强AR的转录活性。然而，HIF-1 α对于低氧激活的AR反式激活是必要的，但不是充分的，并且在去势抵抗性前列腺癌中调节AR功能的分子机制仍不清楚。在这里，我们报告说，β-连环蛋白是所需的低氧LNCaP前列腺癌细胞在低雄激素条件下的HIF-1 α介导的AR反式激活。HIF-1 α和β-连环蛋白协同增强AR N末端和C末端相互作用。β-连环蛋白在去势小鼠中LNCaP异种移植物的HIF-1 α蛋白阳性细胞的细胞核中积累。在LNCaP细胞中，当HIF-1 α被敲低或在细胞质中外源性表达时，低氧诱导的β-连环蛋白核定位被抑制。β-连环蛋白在细胞核和细胞质中与HIF-1 α形成复合物。缺氧增加了由AR和β-连环蛋白组成的复合物的量，并且HIF-1 α的敲低减弱了AR和β-连环蛋白向雄激素应答基因的雄激素应答元件（战神）的募集。此外，在雄激素存在下，HIF-1 α与β-连环蛋白一起与战神结合。这些结果表明：（i）HIF-1 α和β-连环蛋白通过加速N-末端和C-末端相互作用协同增强AR反式激活;（ii）HIF-1 α促进缺氧时β-连环蛋白的核转位;（iii）AR、HIF-1 α和β-连环蛋白在战神上形成三元复合物。
The androgen receptor (AR) acts as a ligand-dependent transcriptional factor and plays a critical role in the development and progression of androgen-dependent and castration-resistant prostate cancer. Castration results in hypoxia in prostate cancer cells, and hypoxia enhances transcriptional activity of AR through hypoxia-inducible factor (HIF)-1 alpha at low serum androgen levels mimicking the castration-resistant stage. However, HIF-1 alpha is necessary but not sufficient for hypoxia-activated AR transactivation, and the molecular mechanism that regulates AR function in castration-resistant prostate cancer remains unclear. Here, we report that beta-catenin is required for HIF-1 alpha mediated AR transactivation in hypoxic LNCaP prostate cancer cells under low androgen conditions. HIF-1 alpha and beta-catenin coordinately enhanced AR N-terminal and C-terminal interaction. beta-Catenin accumulated in the nucleus in the HIF-1 alpha protein-positive cells of LNCaP xenografts in castrated mice. In LNCaP cells, when HIF-1 alpha was knocked down or was exogenously expressed in the cytoplasm, hypoxia-induced nuclear localization of beta-catenin was inhibited. beta-Catenin formed a complex with HIF-1 alpha both in the nucleus and in the cytoplasm. Hypoxia increased the amount of a complex composed of AR and beta-catenin, and knockdown of HIF-1 alpha attenuated the recruitment of AR and beta-catenin to the androgen response elements (AREs) of androgen-responsive genes. Furthermore, together with beta-catenin, HIF-1 alpha bound to the AREs in the presence of androgen. These results demonstrate that (i) HIF-1 alpha and beta-catenin coordinately enhance AR transactivation by accelerating N-terminal and C-terminal interaction; (ii) HIF-1 alpha promotes nuclear translocation of beta-catenin in hypoxia; and (iii) AR, HIF-1 alpha, and beta-catenin form a ternary complex on AREs.