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

Oncogene volume 40, pages 262–276 (2021)Cite this article

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Abstract

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/EBPα, directly binding to C/EBPα, 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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Fig. 1: Relative UBR5 expression in pancreatic cancer and its clinical significance.
Fig. 2: Effects of UBR5 on pancreatic cancer cell growth.
Fig. 3: UBR5 promotes aerobic glycolysis in pancreatic cancer cells.
Fig. 4: Stable knockdown of UBR5 increased FBP1 expression in pancreatic cancer cells.
Fig. 5: Tumour-suppressive effects of UBR5 silencing in pancreatic cancer cells partially reversed by FBP1 knockdown.
Fig. 6: UBR5 regulates FBP1 expression through C/EBPα.
Fig. 7: UBR5 destabilises C/EBPα by promoting C/EBPα ubiquitination and degradation in pancreatic cancer cells.
Fig. 8: Model summarizing the role of UBR5 in pancreatic cancer.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (nos. 81760523, 81560117, 32060166, 81960436 and 81560396), the Project of the Jiangxi Provincial Department of Science and Technology (nos. 20171BAB215024 and 20192BCB23023), the Project of the Jiangxi Provincial Department of Education (no. GJJ160251) and the Project of the Jiangxi Provincial Health Commission (no. 2017A264).

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  1. These authors contributed equally: Leifeng Chen, Rongfa Yuan

Authors and Affiliations

  1. Jiangxi Provincial Clinical Research Center for General Surgery Disease, Nanchang, China

    Leifeng Chen

  2. Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Leifeng Chen, Rongfa Yuan, Chongyu Wen, Tiande Liu, Qian Feng & Xueqiang Deng

  3. Department of Medical, Jiangxi Provincial People’s Hospital of Nanchang University, Nanchang, China

    Yunyan Du

  4. Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Xiaogang Peng

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Correspondence to Yunyan Du or Xiaogang Peng.

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Chen, L., Yuan, R., Wen, C. et al. E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα. Oncogene 40, 262–276 (2021). https://doi.org/10.1038/s41388-020-01527-1

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