Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Oncogene volume 41, pages 5199–5213 (2022)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science. 2019;366:818–22.

    Article  CAS  PubMed  Google Scholar 

  2. Deshaies RJ. Proteotoxic crisis, the ubiquitin-proteasome system, and cancer therapy. BMC Biol. 2014;12:94.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Costa-Mattioli M, Walter P. The integrated stress response: from mechanism to disease. Science. 2020;368:eaat5314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zheng N, Shabek N. Ubiquitin ligases: structure, function, and regulation. Annu Rev Biochem. 2017;86:129–57.

    Article  CAS  PubMed  Google Scholar 

  5. Stewart MD, Ritterhoff T, Klevit RE, Brzovic PS. E2 enzymes: more than just middle men. Cell Res. 2016;26:423–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Osborne HC, Irving E, Forment JV, Schmidt CK. E2 enzymes in genome stability: pulling the strings behind the scenes. Trends Cell Biol. 2021;31:628–43.

    Article  CAS  PubMed  Google Scholar 

  7. Yanagitani K, Juszkiewicz S, Hegde RS. UBE2O is a quality control factor for orphans of multiprotein complexes. Science. 2017;357:472–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nguyen AT, Prado MA, Schmidt PJ, Sendamarai AK, Wilson-Grady JT, Min M, et al. UBE2O remodels the proteome during terminal erythroid differentiation. Science. 2017;357:eaan0218.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Vila IK, Yao Y, Kim G, Xia W, Kim H, Kim SJ, et al. A UBE2O-AMPKalpha2 axis that promotes tumor initiation and progression offers opportunities for therapy. Cancer Cell. 2017;31:208–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Faust TB, Li Y, Bacon CW, Jang GM, Weiss A, Jayaraman B, et al. The HIV-1 Tat protein recruits a ubiquitin ligase to reorganize the 7SK snRNP for transcriptional activation. eLife. 2018;7:e31879.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Huang Y, Yang X, Lu Y, Zhao Y, Meng R, Zhang S, et al. UBE2O targets Mxi1 for ubiquitination and degradation to promote lung cancer progression and radioresistance. Cell Death Differ. 2021;28:671–84.

    Article  CAS  PubMed  Google Scholar 

  12. Liu X, Ma F, Liu C, Zhu K, Li W, Xu Y, et al. UBE2O promotes the proliferation, EMT and stemness properties of breast cancer cells through the UBE2O/AMPKalpha2/mTORC1-MYC positive feedback loop. Cell Death Dis. 2020;11:10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yokota T, Nagai H, Harada H, Mine N, Terada Y, Fujiwara H, et al. Identification, tissue expression, and chromosomal position of a novel gene encoding human ubiquitin-conjugating enzyme E2-230k. Gene. 2001;267:95–100.

    Article  CAS  PubMed  Google Scholar 

  14. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73:4–13.

    Article  CAS  PubMed  Google Scholar 

  15. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

    Article  PubMed  Google Scholar 

  16. Osada T, Sakamoto M, Nishibori H, Iwaya K, Matsuno Y, Muto T, et al. Increased ubiquitin immunoreactivity in hepatocellular carcinomas and precancerous lesions of the liver. J Hepatol. 1997;26:1266–73.

    Article  CAS  PubMed  Google Scholar 

  17. Lectez B, Migotti R, Lee SY, Ramirez J, Beraza N, Mansfield B, et al. Ubiquitin profiling in liver using a transgenic mouse with biotinylated ubiquitin. J Proteome Res. 2014;13:3016–26.

    Article  CAS  PubMed  Google Scholar 

  18. Shirahashi H, Sakaida I, Terai S, Hironaka K, Kusano N, Okita K. Ubiquitin is a possible new predictive marker for the recurrence of human hepatocellular carcinoma. Liver. 2002;22:413–8.

    Article  CAS  PubMed  Google Scholar 

  19. Uhlen M, Zhang C, Lee S, Sjostedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357:aan2507.

    Article  Google Scholar 

  20. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–W102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Villa E, Critelli R, Lei B, Marzocchi G, Camma C, Giannelli G, et al. Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study. Gut. 2016;65:861–9.

    Article  CAS  PubMed  Google Scholar 

  22. Lim HY, Sohn I, Deng S, Lee J, Jung SH, Mao M, et al. Prediction of disease-free survival in hepatocellular carcinoma by gene expression profiling. Ann Surg Oncol. 2013;20:3747–53.

    Article  PubMed  Google Scholar 

  23. Minguez B, Hoshida Y, Villanueva A, Toffanin S, Cabellos L, Thung S, et al. Gene-expression signature of vascular invasion in hepatocellular carcinoma. J Hepatol. 2011;55:1325–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ma M, Xu H, Liu G, Wu J, Li C, Wang X, et al. Metabolism-induced tumor activator 1 (MITA1), an energy stress-inducible long noncoding RNA, promotes hepatocellular carcinoma metastasis. Hepatology. 2019;70:215–30.

    CAS  PubMed  Google Scholar 

  25. Mashtalir N, Daou S, Barbour H, Sen NN, Gagnon J, Hammond-Martel I, et al. Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O. Mol Cell. 2014;54:392–406.

    Article  CAS  PubMed  Google Scholar 

  26. Chen S, Yang J, Zhang Y, Duan C, Liu Q, Huang Z, et al. Ubiquitin-conjugating enzyme UBE2O regulates cellular clock function by promoting the degradation of the transcription factor BMAL1. J Biol Chem. 2018;293:11296–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khare T, Khare S, Angdisen JJ, Zhang Q, Stuckel A, Mooney BP, et al. Defects in long-chain 3-hydroxy acyl-CoA dehydrogenase lead to hepatocellular carcinoma: a novel etiology of hepatocellular carcinoma. Int J Cancer. 2020;147:1461–73.

    Article  CAS  PubMed  Google Scholar 

  28. Liu S, Liu X, Wu F, Zhang X, Zhang H, Gao D, et al. HADHA overexpression disrupts lipid metabolism and inhibits tumor growth in clear cell renal cell carcinoma. Exp Cell Res. 2019;384:111558.

    Article  CAS  PubMed  Google Scholar 

  29. Tanaka M, Masaki Y, Tanaka K, Miyazaki M, Kato M, Sugimoto R, et al. Reduction of fatty acid oxidation and responses to hypoxia correlate with the progression of de-differentiation in HCC. Mol Med Rep. 2013;7:365–70.

    Article  CAS  PubMed  Google Scholar 

  30. Gao Q, Zhu H, Dong L, Shi W, Chen R, Song Z, et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma. Cell. 2019;179:561–77.

    Article  CAS  PubMed  Google Scholar 

  31. Pan A, Sun XM, Huang FQ, Liu JF, Cai YY, Wu X, et al. The mitochondrial beta-oxidation enzyme HADHA restrains hepatic glucagon response by promoting beta-hydroxybutyrate production. Nat Commun. 2022;13:386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liu J, Zhang Y, Tian Y, Huang W, Tong N, Fu X. Integrative biology of extracellular vesicles in diabetes mellitus and diabetic complications. Theranostics. 2022;12:1342–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Meng Z, Ma X, Du J, Wang X, He M, Gu Y, et al. CAMK2gamma antagonizes mTORC1 activation during hepatocarcinogenesis. Oncogene. 2017;36:2446–56.

    Article  CAS  PubMed  Google Scholar 

  34. Liu X, Liu J, Xiao W, Zeng Q, Bo H, Zhu Y, et al. SIRT1 regulates N(6) -methyladenosine RNA modification in hepatocarcinogenesis by inducing RANBP2-dependent FTO SUMOylation. Hepatology. 2020;72:2029–50.

    Article  CAS  PubMed  Google Scholar 

  35. Wang J, Wang H, Peters M, Ding N, Ribback S, Utpatel K, et al. Loss of Fbxw7 synergizes with activated Akt signaling to promote c-Myc dependent cholangiocarcinogenesis. J Hepatol. 2019;71:742–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu Y, Tao S, Liao L, Li Y, Li H, Li Z, et al. TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway. Nat Commun. 2020;11:348.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Yu H, Li M, He R, Fang P, Wang Q, Yi Y, et al. Major vault protein promotes hepatocellular carcinoma through targeting interferon regulatory factor 2 and decreasing p53 activity. Hepatology. 2020;72:518–34.

    Article  CAS  PubMed  Google Scholar 

  38. Muto Y, Moroishi T, Ichihara K, Nishiyama M, Shimizu H, Eguchi H, et al. Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis. J Exp Med. 2019;216:950–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liang K, Volk AG, Haug JS, Marshall SA, Woodfin AR, Bartom ET, et al. Therapeutic targeting of MLL degradation pathways in MLL-rearranged leukemia. Cell. 2017;168:59–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hao YH, Doyle JM, Ramanathan S, Gomez TS, Jia D, Xu M, et al. Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination. Cell. 2013;152:1051–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xu H, Shi J, Gao H, Liu Y, Yang Z, Shao F, et al. The N-end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome activation by anthrax lethal toxin. EMBO J. 2019;38:e101996.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Shi Z, Liu R, Lu Q, Zeng Z, Liu Y, Zhao J, et al. UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKalpha2/mTOR pathway. Int J Med Sci. 2021;18:3749–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Vila IK, Park MK, Setijono SR, Yao Y, Kim H, Badin PM, et al. A muscle-specific UBE2O/AMPKalpha2 axis promotes insulin resistance and metabolic syndrome in obesity. JCI Insight. 2019;4:e128269.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kim Y, Williams KC, Gavin CT, Jardine E, Chambers AF, Leong HS. Quantification of cancer cell extravasation in vivo. Nat Protoc. 2016;11:937–48.

    Article  CAS  PubMed  Google Scholar 

  45. Xia C, Fu Z, Battaile KP, Kim JP. Crystal structure of human mitochondrial trifunctional protein, a fatty acid beta-oxidation metabolon. Proc Natl Acad Sci USA. 2019;116:6069–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ljubkovic M, Gressette M, Bulat C, Cavar M, Bakovic D, Fabijanic D, et al. Disturbed fatty acid oxidation, endoplasmic reticulum stress, and apoptosis in left ventricle of patients with type 2 diabetes. Diabetes. 2019;68:1924–33.

    Article  CAS  PubMed  Google Scholar 

  47. Miklas JW, Clark E, Levy S, Detraux D, Leonard A, Beussman K, et al. TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes. Nat Commun. 2019;10:4671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yamamoto K, Abe S, Honda A, Hashimoto J, Aizawa Y, Ishibashi S, et al. Fatty acid beta oxidation enzyme HADHA is a novel potential therapeutic target in malignant lymphoma. Lab Invest. 2020;100:353–62.

    Article  CAS  PubMed  Google Scholar 

  49. Amoedo ND, Sarlak S, Obre E, Esteves P, Begueret H, Kieffer Y, et al. Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas. J Clin Invest. 2021;131:e133081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yokoyama Y, Kuramitsu Y, Takashima M, Iizuka N, Toda T, Terai S, et al. Proteomic profiling of proteins decreased in hepatocellular carcinoma from patients infected with hepatitis C virus. Proteomics. 2004;4:2111–6.

    Article  CAS  PubMed  Google Scholar 

  51. Liu Y, Lu LL, Wen D, Liu DL, Dong LL, Gao DM, et al. MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming. J Hematol Oncol. 2020;13:12.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  53. Chi Z, Chen S, Xu T, Zhen W, Yu W, Jiang D, et al. Histone deacetylase 3 couples mitochondria to drive IL-1beta-dependent inflammation by configuring fatty acid oxidation. Mol Cell. 2020;80:43–58.

    Article  CAS  PubMed  Google Scholar 

  54. Mi B, Chen L, Xiong Y, Yan C, Xue H, Panayi AC, et al. Saliva exosomes-derived UBE2O mRNA promotes angiogenesis in cutaneous wounds by targeting SMAD6. J Nanobiotechnology. 2020;18:68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Xu H, Du X, Xu J, Zhang Y, Tian Y, Liu G, et al. Pancreatic beta cell microRNA-26a alleviates type 2 diabetes by improving peripheral insulin sensitivity and preserving beta cell function. PLoS Biol. 2020;18:e3000603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tian Y, Zhang M, Fan M, Xu H, Wu S, Zou S, et al. A miRNA-mediated attenuation of hepatocarcinogenesis in both hepatocytes and Kupffer cells. Mol Ther Nucleic Acids. 2022;30:1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, Sichuan, China

    Meilin Ma, Rong Cao, Dongmei Tang, Xiongbo Sang, Sailan Zou, Haixia Xu, Geng Liu, Yan Tian & Xianghui Fu

  2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, Sichuan, China

    Changhui Zhang, Xiuxuan Wang & Lunzhi Dai

  3. Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, Sichuan, China

    Xiang Gao

Authors
  1. Meilin Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Changhui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rong Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dongmei Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiongbo Sang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sailan Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiuxuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Haixia Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Geng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lunzhi Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yan Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xiang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xianghui Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding authors

Correspondence to Xiang Gao or Xianghui Fu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02509-1

This article is cited by

Search

Advanced search

Quick links