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UBE2O promotes lipid metabolic reprogramming and liver cancer progression by mediating HADHA ubiquitination

Abstract

Cancer cells rely on heightened protein quality control mechanisms, including the ubiquitin-proteosome system that is predominantly driven by ubiquitination comprising E1, E2, and E3 trienzyme cascades. Although E3s have been extensively studied, the implication of E2s in tumorigenesis is poorly defined. Here we reveal a critical E2 in the pathogenesis of hepatocellular carcinoma (HCC). Among all of E2s, UBE2O shows the strongest association with HCC survival prognosis, and its expression is increased in HCC tumors. Accordingly, UBE2O deficiency inhibits HCC growth and metastasis both in vitro and in vivo, while its overexpression has opposite effects. Depending on both E2 and E3 enzymatic activities, UBE2O can interact with and mediate the ubiquitination and degradation of HADHA, a mitochondrial β-oxidation enzyme, thereby modulating lipid metabolic reprogramming. HADHA is reduced in HCC tumors and inversely correlated with UBE2O levels. Importantly, HADHA acts as a tumor suppressor and primarily mediates UBE2O’s function on HCC. Moreover, liver-specific deletion of Ube2o in mice are resistant to DEN-induced hepatocarcinogenesis, along with HADHA upregulation and reduced hepatic lipid accumulation. These data reveal UBE2O as a novel oncogenic driver for metabolic reprogramming and HCC development, highlighting the potential of targeting UBE2O/HADHA axis for HCC therapy.

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Fig. 1: UBE2O is upregulated in HCC and predicts poor survival.
Fig. 2: UBE2O promotes HCC growth and metastasis in vitro and in vivo.
Fig. 3: UBE2O enhances HCC metastasis in vitro and in vivo.
Fig. 4: UBE2O interacts with HADHA.
Fig. 5: UBE2O ubiquitinates HADHA for degradation.
Fig. 6: HADHA inhibits HCC growth and metastasis and is indispensable for the effects of UBE2O in HCC progression.
Fig. 7: UBE2O promotes lipid metabolism reprogramming of HCC cells through inactivation of HADHA.
Fig. 8: UBE2O-HADHA-lipid reprogramming regulatory axis in mouse primary HCC.

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Acknowledgements

We thank Dr. Hongbo Hu for kindly providing WT and mutant ubiquitin-overexpression plasmids.

Funding

This work was supported by the National Natural Science Foundation of China (82103128, 92157205, 81970561, and 81802836), the National Key Research and Development Program of China (2018YFC2000305), the Ministry of Science and Technology of China (2018ZX09201018-005), China National Postdoctoral Program for Innovative Talents (BX2021201), China Postdoctoral Science Foundation (2021M692302), the 1.3.5 Project for Disciplines Excellence, West China Hospital, Sichuan University (ZYJC18049), Sichuan Science & Technology Program (2019JDTD0013), and the Post-Doctor Research Project, West China Hospital, Sichuan University (2020HXBH121).

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XF and YT conceived the project. MM and CZ designed the experiments and analyzed the data. RC, DT, XS, SZ, XW, HX and GL performed the experiments, in part, and analyzed the data. LD helped perform the analysis with constructive discussions. XF, YT and XG supervised the study. XF, YT and MM wrote and revised the manuscript.

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Correspondence to Xiang Gao or Xianghui Fu.

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Ma, M., Zhang, C., Cao, R. et al. UBE2O promotes lipid metabolic reprogramming and liver cancer progression by mediating HADHA ubiquitination. Oncogene 41, 5199–5213 (2022). https://doi.org/10.1038/s41388-022-02509-1

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