Hypoxia enhances transcriptional activity of androgen receptor through hypoxia-inducible factor-1α in a low androgen environment
Hypoxia enhances transcriptional activity of androgen receptor through hypoxia-inducible factor-1α in a low androgen environment
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DOI：
10.1016/j.jsbmb.2010.10.009
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发表时间：
2011-01-01
影响因子：
4.1
通讯作者：
Inui, Hiroshi
中科院分区：
文献类型：
--
作者：
Mitani, Takakazu;Yamaji, Ryoichi;Inui, Hiroshi
雄激素受体（AR）作为一种配体依赖性转录因子，控制前列腺癌的发生或进展。通过去势的雄激素消融是前列腺癌的有效疗法，而最终大多数肿瘤从对雄激素敏感的疾病状态转化为对雄激素难治的疾病状态，并且甚至在低雄激素环境中生长（例如，0.1 nM 5 α-二氢睾酮（DHT）），如去势抵抗期。雄激素消融导致缺氧，并且实体瘤具有缺氧环境。低氧诱导因子（HIF）-1由HIF-1 α和HIF-1 β/ARNT亚单位组成，是低氧诱导基因的主要转录因子。在这里，我们报告说，缺氧增强AR反式激活的存在下，0.05和0.1 nM的DHT在LNCaP前列腺癌细胞。siRNA介导的HIF-1 α敲低抑制缺氧增强的AR反式激活。HIF-1 α siRNA的抑制作用被HIF-1 α siRNA抗性形式的表达所抵消。HIF-1 α siRNA抑制缺氧刺激的雄激素反应性NKX3.1基因的表达，在0.1 nM的DHT的存在下，但不是在没有DHT。在缺氧条件下，HIF-1 α siRNA抑制的AR反式激活在HIF-1 α缺乏DNA结合活性的突变体中恢复。此外，HIF-1 α的显性负性形式取消了缺氧增强的AR反式激活，HIF-1 β/ARNT siRNA对缺氧增强的AR反式激活没有影响。这些结果表明，缺氧导致HIF-1 α介导的AR反式激活，与HIF-1活性无关，并且HIF-1 β/ARNT不一定是反式激活所必需的。(C)2010爱思唯尔有限公司版权所有。
The androgen receptor (AR) acts as a ligand-dependent transcriptional factor controlling development or progression of prostate cancer. Androgen ablation by castration is an effective therapy for prostate cancer, whereas eventually most of the tumors convert from a hormone-sensitive to a hormone-refractory disease state and grow even in a low androgen environment (e.g., 0.1 nM 5 alpha-dihydrotestosterone (DHT)) like the castration-resistant stage. Androgen ablation results in hypoxia, and solid tumors possess hypoxic environments. Hypoxia-inducible factor (HIF)-1, which is composed of HIF-1 alpha and HIF-1 beta/ARNT sub-units, functions as a master transcription factor for hypoxia-inducible genes. Here, we report that hypoxia enhances AR transactivation in the presence of 0.05 and 0.1 nM DHT in LNCaP prostate cancer cells. siRNA-mediated knockdown of HIF-1 alpha inhibited hypoxia-enhanced AR transactivation. Its inhibition by HIF-1 alpha siRNA was canceled by expression of a siRNA-resistant form of HIF-1 alpha. HIF-1 alpha siRNA repressed hypoxia-stimulated expression of the androgen-responsive NKX3.1 gene in the presence of 0.1 nM DHT, but not in the absence of DHT. In hypoxia, HIF-1 alpha siRNA-repressed AR transactivation was restored in mutants in which HIF-1 alpha lacked DNA-binding activity. Furthermore, a dominant negative form of HIF-1 alpha canceled hypoxia-enhanced AR transactivation, and HIF-1 beta/ARNT siRNAs had no influence on hypoxia-enhanced AR transactivation. These results indicate that hypoxia leads to HIF-1 alpha-mediated AR transactivation independent of HIF-1 activity and that HIF-1 beta/ARNT is not necessarily required for the transactivation. (C) 2010 Elsevier Ltd. All rights reserved.