Hyperactivation of Notch signaling and the cellular hypoxic response are frequently observed in cancers, with increasing reports of connections to tumor initiation and progression. The two signaling mechanisms are known to intersect, but while it is well established that hypoxia regulates Notch signaling, less is known about whether Notch can regulate the cellular hypoxic response. We now report that Notch signaling specifically controls expression of HIF2α, a key mediator of the cellular hypoxic response. Transcriptional upregulation of HIF2α by Notch under normoxic conditions leads to elevated HIF2α protein levels in primary breast cancer cells as well as in human breast cancer, medulloblastoma, and renal cell carcinoma cell lines. The elevated level of HIF2α protein was in certain tumor cell types accompanied by downregulation of HIF1α protein levels, indicating that high Notch signaling may drive a HIF1α-to-HIF2α switch. At the transcriptome level, the presence of HIF2α was required for approximately 21% of all Notch-induced genes: among the 1062 genes that were upregulated by Notch in medulloblastoma cells during normoxia, upregulation was abrogated in 227 genes when HIF2α expression was knocked down by HIF2α siRNA. In conclusion, our data show that Notch signaling affects the hypoxic response via regulation of HIF2α, which may be important for future cancer therapies.

中文翻译：

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Notch信号在多种肿瘤细胞类型中促进HIF2α驱动的缺氧反应。

在癌症中经常观察到Notch信号的过度激活和细胞缺氧反应，与肿瘤的发生和发展有关的报道越来越多。已知两种信号传导机制是相交的，但是尽管已经充分确定缺氧可以调节Notch信号传导，但是对于Notch是否可以调节细胞低氧反应的了解却很少。现在我们报道，Notch信号特异性控制HIF2α的表达，HIF2α是细胞缺氧反应的关键介体。Notch在常氧条件下转录上调HIF2α会导致原发性乳腺癌细胞以及人乳腺癌，髓母细胞瘤和肾细胞癌细胞系中HIF2α蛋白水平升高。HIF2α蛋白的水平升高是在某些肿瘤细胞类型中，伴随着HIF1α蛋白水平的下调，这表明高的Notch信号可能驱动HIF1α向HIF2α的转换。在转录组水平上，所有Notch诱导的基因中约21％需要HIF2α的存在：在常氧性髓母细胞瘤细胞中Notch上调的1062个基因中，当通过敲除HIF2α的表达时，227个基因中止了上调HIF2αsiRNA。总之，我们的数据表明，Notch信号通过调节HIF2α影响缺氧反应，这可能对未来的癌症治疗很重要。在常氧性髓母细胞瘤细胞中Notch上调的1062个基因中，当HIF2αsiRNA敲低HIF2α表达时，227个基因中的上调被消除。总之，我们的数据表明，Notch信号通过调节HIF2α影响缺氧反应，这可能对未来的癌症治疗很重要。在常氧性髓母细胞瘤细胞中Notch上调的1062个基因中，当HIF2αsiRNA敲低HIF2α表达时，227个基因中的上调被消除。总之，我们的数据表明，Notch信号通过调节HIF2α影响缺氧反应，这可能对未来的癌症治疗很重要。