4.8 Article

E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα

Journal

ONCOGENE
Volume 40, Issue 2, Pages 262-276

Publisher

SPRINGERNATURE
DOI: 10.1038/s41388-020-01527-1

Keywords

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Funding

  1. National Natural Science Foundation of China [81760523, 81560117, 32060166, 81960436, 81560396]
  2. Project of the Jiangxi Provincial Department of Science and Technology [20171BAB215024, 20192BCB23023]
  3. Project of the Jiangxi Provincial Department of Education [GJJ160251]
  4. Project of the Jiangxi Provincial Health Commission [2017A264]

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In pancreatic cancer patients, UBR5 levels were significantly upregulated and closely related to the malignant phenotype and shorter survival. UBR5 contributes to the growth of pancreatic cancer cells by inducing aerobic glycolysis and regulates FBP1 expression by modulating C/EBP alpha.
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.

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