E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα
E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα
复制标题
E3 泛素连接酶 UBR5 通过 C/EBPα 的不稳定下调 FBP1，促进胰腺癌生长和有氧糖酵解。
DOI：
10.1038/s41388-020-01527-1
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发表时间：
2020-10-29
期刊：
影响因子：
8
通讯作者：
Peng, Xiaogang
中科院分区：
文献类型：
--
作者：
Chen, Leifeng;Yuan, Rongfa;Peng, Xiaogang
胰腺癌是人类最致命的癌症之一。虽然它在营养不良的状态下茁壮成长，但胰腺癌细胞通过代谢重编程适应代谢应激的机制仍不清楚。在这里，我们发现UBR 5，一种E3泛素连接酶，在胰腺癌患者样本中与邻近正常组织中的水平相比显著上调。UBR 5水平与胰腺癌患者的恶性表型和较短的生存期密切相关。多变量分析还显示，UBR 5过表达是胰腺癌患者预后不良的独立预测因子。功能分析显示，UBR 5通过诱导有氧糖酵解促进胰腺癌细胞的生长。此外，我们证明了UBR 5敲低增加了果糖-1，6-二磷酸酶（FBP 1）的水平，这是许多癌症中有氧糖酵解过程中的重要负调节因子。我们发现UBR 5和FBP 1水平之间存在显著的负相关性，进一步证明了胰腺癌细胞中UBR 5诱导的有氧糖酵解依赖于FBP 1。从机制上讲，UBR 5通过调节C/EBP α、直接结合C/EBP α并促进其泛素化和降解来调节FBP 1表达。总之，这些结果确定了胰腺癌细胞在营养不良的肿瘤微环境中生存的机制，并提供了关于UBR 5在胰腺癌细胞适应代谢应激中的作用的见解。
Pancreatic cancer is one of the most fatal cancers in humans. While it thrives in a state of malnutrition, the mechanism by which pancreatic cancer cells adapt to metabolic stress through metabolic reprogramming remains unclear. Here, we showed that UBR5, an E3 ubiquitin ligase, was significantly upregulated in pancreatic cancer patient samples compared to the levels in adjacent normal tissues. Levels of UBR5 were closely related to a malignant phenotype and shorter survival among pancreatic cancer patients. Multivariate analyses also revealed that UBR5 overexpression was an independent predictor of poor outcomes among patients with pancreatic cancer. Functional assays revealed that UBR5 contributes to the growth of pancreatic cancer cells by inducing aerobic glycolysis. Furthermore, we demonstrated that UBR5 knockdown increased levels of fructose-1,6-bisphosphatase (FBP1), an important negative regulator in the process of aerobic glycolysis in many cancers. We found a significant negative correlation between levels of UBR5 and FBP1, further demonstrating that UBR5-induced aerobic glycolysis is dependent on FBP1 in pancreatic cancer cells. Mechanistically, UBR5 regulates FBP1 expression by modulating C/EBP alpha, directly binding to C/EBP alpha, and promoting its ubiquitination and degradation. Together, these results identify a mechanism used by pancreatic cancer cells to survive the nutrient-poor tumour microenvironment and also provide insight regarding the role of UBR5 in pancreatic cancer cell adaptation to metabolic stresses.