Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells.
Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells.
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DOI：
10.1016/j.stemcr.2016.03.004
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发表时间：
2016-05-10
影响因子：
5.9
通讯作者：
Lendahl U
中科院分区：
文献类型：
--
作者：
Braune EB;Tsoi YL;Phoon YP;Landor S;Silva Cascales H;Ramsköld D;Deng Q;Lindqvist A;Lian X;Sahlgren C;Jin SB;Lendahl U
Notch信号是干细胞分化的重要调控因子。所有典型的Notch信号都是通过dna结合蛋白CSL传递的，过度激活的Notch信号与肿瘤的发生有关；因此，可以预期CSL缺乏应该会减少肿瘤的生长。相反，我们报告了乳腺肿瘤细胞中基因去除CSL导致异种移植肿瘤加速生长。在常氧条件下，CSL的缺失释放出缺氧反应，表现为HIF1α蛋白的稳定和多倍体巨细胞的获得，类似癌症干细胞的表型。在转录组水平上，CSL缺失上调了超过1750个基因，其中不到3%的基因是Notch转录特征的一部分。综上所述，这表明CSL除了作为Notch信号级联的中心节点外，还具有其他功能，并揭示了CSL在肿瘤发生和细胞缺氧反应调节中的作用。CSL缺失加速肿瘤生长CSL缺失在常氧环境下引发低氧反应CSL缺失导致多倍体巨细胞、癌干细胞样形态CSL缺失细胞表现出notch -不依赖的转录特征在本报告中，Lendahl、Jin和同事发现CSL缺失（RBP-Jk）在体内促进肿瘤生长，并为CSL在控制细胞缺氧反应和细胞周期/细胞分裂中的作用提供了证据。此外，他们表明CSL的缺失不仅仅介导Notch信号传导。
Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL, and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1α protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1,750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a role for CSL in tumorigenesis and regulation of the cellular hypoxic response. Loss of CSL accelerates tumor growth CSL deficiency unleashes a hypoxic response during normoxia Loss of CSL leads to a polyploid giant-cell, cancer stem cell-like morphology CSL-deficient cells show a Notch-independent transcriptional signature In this report, Lendahl, Jin, and colleagues show that the loss of CSL (RBP-Jk) promotes tumor growth in vivo and provide evidence for a role of CSL in controlling the cellular hypoxic response and cell cycle/cytokinesis. Furthermore, they show that loss of CSL acts beyond only mediating Notch signaling.