FoxM1, a critical regulator of oxidative stress during oncogenesis
FoxM1, a critical regulator of oxidative stress during oncogenesis
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DOI：
10.1038/emboj.2009.239
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发表时间：
2009-10-07
期刊：
影响因子：
11.4
通讯作者：
Raychaudhuri, Pradip
中科院分区：
文献类型：
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作者：
Park, Hyun Jung;Carr, Janai R.;Raychaudhuri, Pradip
转录因子FOXM1在大多数人类恶性肿瘤中过度表达。虽然FOXM1显然在肿瘤的发展和进展中具有关键功能，但FOXM1参与这些过程的机制尚不清楚。在这里，我们描述了FOXM1在氧化应激调节中的重要作用，氧化应激有助于恶性转化和肿瘤细胞生存。我们发现了一个涉及FOXM1的负反馈环，它调节增殖细胞中的活性氧物种(ROS)。我们表明，致癌RAS对FOXM1的诱导需要ROS。FOXM1的升高反过来又通过刺激ROS清道夫基因的表达而下调ROS水平，如MnSOD、过氧化氢酶和PRDX3。FOXM1缺失使细胞对氧化应激敏感，并增加癌基因诱导的过早衰老。此外，表达激活的AKT1的肿瘤细胞对FOXM1上瘾，因为它们需要持续存在FOXM1才能生存。综上所述，我们的结果确定FOXM1是ROS在细胞分裂中的关键调节因子，并为肿瘤细胞如何使用FOXM1控制氧化应激以逃避早衰和凋亡的机制提供了见解。EMBO期刊(2009)28,2908-2918。DOI：10.1038/Exempj.2009.239；2009年8月20日在线发布
The transcription factor FoxM1 is over-expressed in most human malignancies. Although it is evident that FoxM1 has critical functions in tumour development and progression, the mechanisms by which FoxM1 participates in those processes are not understood. Here, we describe an essential role of FoxM1 in the regulation of oxidative stress that contributes to malignant transformation and tumour cell survival. We identify a negative feedback loop involving FoxM1 that regulates reactive oxygen species (ROS) in proliferating cells. We show that induction of FoxM1 by oncogenic Ras requires ROS. Elevated FoxM1, in turn, downregulates ROS levels by stimulating expression of ROS scavenger genes, such as MnSOD, catalase and PRDX3. FoxM1 depletion sensitizes cells to oxidative stress and increases oncogene-induced premature senescence. Moreover, tumour cells expressing activated AKT1 are 'addicted' to FoxM1, as they require continuous presence of FoxM1 for survival. Together, our results identify FoxM1 as a key regulator of ROS in dividing cells, and provide insights into the mechanism how tumour cells use FoxM1 to control oxidative stress to escape premature senescence and apoptosis. The EMBO Journal (2009) 28, 2908-2918. doi: 10.1038/emboj.2009.239; Published online 20 August 2009