Reply to correspondence on “UBE2S: A novel driver of HIF-1alpha-induced metabolic reprogramming in hepatocellular carcinoma”

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Clin Mol Hepatol. 2025;31(1):e119-e120
Publication date (electronic) : 2024 August 5
doi : https://doi.org/10.3350/cmh.2024.0621
1Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
2State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong
Corresponding author : Terence Kin Wah Lee Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Room 805, Block Y, Lee Shau Kee Building, Hong Kong Tel: +852-3400-8799, Fax: +852-2364-9932, E-mail: terence.kw.lee@polyu.edu.hk
Editor: Han Ah Lee, Chung-Ang University College of Medicine, Korea
Received 2024 August 1; Accepted 2024 August 4.

Dear Editor,

I would like to appreciate Renyu Zhang, Ding Wei, Zhinan Chen, Huijie Bian for their Correspondence [1] as a reply to my editorial entitled “UBE2S: A novel driver of HIF-1alpha-induced metabolic reprogramming in hepatocellular carcinoma [2].” I was deeply interested in reading the Correspondence as a cancer biologist specializing in liver cancer research. It is intriguing to demonstrate that UBE2S promotes HIF-1α-driven glycolysis in hepatocellular carcinoma (HCC) cells by disrupting von Hippel-Lindau tumor suppressor (VHL) protein stability and enhancing β-catenin protein stability. Based on a previous study by Berndt et al. [3], there is a possible interaction between the VHL and β-catenin. The observation of higher β-catenin levels in UBE2S overexpressing HCC cells could be attributed to reduced VHL-induced ubiquitylation via Jade-1. The results also suggested the inhibition of various pathways, such as HIF-1α, glycolysis, and β-catenin, through the targeting of UBE2S. Based on the novel findings presented by Zhang et al. [4] showing the interplay of UBE2S/VHL/β-catenin/HIF-1α in driving glycolysis in HCC, further investigations to examine the therapeutic efficacy of targeting this signaling pathway in PDTX and immunocompetent mouse HCC models are warranted. I would like to conclude this Reply by expressing my gratitude to the responses of Zhang and the colleagues for providing further mechanistic insight and therapeutic implications for the role of UBE2S in HCC.

Notes

Authors’ contribution

M.M.L drafted the manuscript. T.K.L reviewed and finalized the manuscript.

Conflicts of Interest

The authors have no conflicts to disclose.

Acknowledgements

This work was supported by the Research Impact Fund (C5008-22F) and the RGC General Research Fund (15104023).

Abbreviations

HCC

hepatocellular carcinoma

VHL

von Hippel–Lindau tumor suppressor

References

1. Zhang R, Wei D, Chen Z, Bian H. Correspondence to editorial on “UBE2S promotes glycolysis in hepatocellular carcinoma by enhancing E3 enzyme-independent polyubiquitination of VHL”. Clin Mol Hepatol 2025;31:e58–e60.
2. Lei MML, Lee TKW. UBE2S: A novel driver of HIF-1alpha-induced metabolic reprogramming in hepatocellular carcinoma: Editorial on “UBE2S promotes glycolysis in hepatocellular carcinoma by enhancing E3 enzyme-independent polyubiquitination of VHL”. Clin Mol Hepatol 2025;31:281–285.
3. Berndt JD, Moon RT, Major MB. Beta-catenin gets jaded and von Hippel-Lindau is to blame. Trends Biochem Sci 2009;34:101–104.
4. Zhang R, Li C, Zhang S, Kong L, Liu Z, Guo Y, et al. UBE2S promotes glycolysis in hepatocellular carcinoma by enhancing E3 enzyme-independent polyubiquitination of VHL. Clin Mol Hepatol 2024;30:771–792.

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