EAF2 Suppresses Hypoxia-Induced Factor 1 α Transcriptional Activity by Disrupting Its Interaction with Coactivator CBP/p300
EAF2 Suppresses Hypoxia-Induced Factor 1 α Transcriptional Activity by Disrupting Its Interaction with Coactivator CBP/p300
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DOI：
10.1128/mcb.00718-13
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发表时间：
2014-03-01
影响因子：
5.3
通讯作者：
Xiao, Wuhan
中科院分区：
文献类型：
--
作者：
Chen, Zhu;Liu, Xing;Xiao, Wuhan
以前的研究表明，潜在的肿瘤抑制因子EAF 2结合并稳定pVHL，这表明EAF 2可能通过干扰缺氧信号通路发挥作用。然而，EAF 2影响缺氧的程度和这种活性的机制仍然很大程度上未知。在本研究中，我们发现EAF 2是一个缺氧反应基因，其启动子中含有缺氧反应元件（HRE）。通过利用pVHL无效细胞系RCC 4和786-O，我们证明了缺氧诱导因子1 α（HIF-1 α），而不是HIF-2 α，在缺氧条件下诱导EAF 2。随后的实验表明，EAF 2结合并抑制HIF-1 α，但不抑制HIF-2 α的反式活性。此外，我们观察到EAF 2抑制HIF-1活性是由于p300募集的破坏，并且这独立于FIH-1（抑制HIF-1的因子）和Sirt 1发生。此外，我们发现EAF 2保护细胞免受缺氧诱导的细胞死亡，并在缺氧条件下抑制细胞对葡萄糖的摄取，这表明EAF 2确实可能通过调节缺氧信号通路发挥作用。我们的研究结果不仅揭示了EAF 2和HIF-1 α之间独特的反馈调节回路，还为EAF 2肿瘤抑制机制提供了新的见解。
Previous studies revealed that the potential tumor suppressor EAF2 binds to and stabilizes pVHL, suggesting that EAF2 may function by disturbing the hypoxia signaling pathway. However, the extent to which EAF2 affects hypoxia and the mechanisms underlying this activity remain largely unknown. In this study, we found that EAF2 is a hypoxia response gene harboring the hypoxia response element (HRE) in its promoter. By taking advantage of the pVHL-null cell lines RCC4 and 786-O, we demonstrated that hypoxia-induced factor 1 alpha (HIF-1 alpha), but not HIF-2 alpha, induced EAF2 under hypoxia. Subsequent experiments showed that EAF2 bound to and suppressed HIF-1 alpha but not HIF-2 alpha transactivity. In addition, we observed that EAF2 inhibition of HIF-1 activity resulted from the disruption of p300 recruitment and that this occurred independently of FIH-1 (factor inhibiting HIF-1) and Sirt1. Furthermore, we found that EAF2 protected cells against hypoxia-induced cell death and inhibited cellular uptake of glucose under hypoxic conditions, suggesting that EAF2 indeed may act by modulating the hypoxia-signaling pathway. Our findings not only uncover a unique feedback regulation loop between EAF2 and HIF-1 alpha but also provide a novel insight into the mechanism of EAF2 tumor suppression.