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. 2025 Jul 1;82(1):42-58.
doi: 10.1097/HEP.0000000000001096. Epub 2024 Sep 30.

Integrated ubiquitomics characterization of hepatocellular carcinomas

Xiao-Tong Lin  1 , Yuan-Deng Luo  1   2 , Cui Mao  1 , Yi Gong  1 , Yu Hou  1   3 , Lei-Da Zhang  1 , Yong-Peng Gu  1 , Di Wu  1 , Jie Zhang  1 , Yu-Jun Zhang  1 , De-Hong Tan  1 , Chuan-Ming Xie  1
Affiliations

Integrated ubiquitomics characterization of hepatocellular carcinomas

Xiao-Tong Lin et al. Hepatology. .

Abstract

Background and aims: Patients with aggressive HCC have limited therapeutic options. Therefore, a better understanding of HCC pathogenesis is needed to improve treatment. Genomic studies of HCC have improved our understanding of cancer biology. However, the ubiquitomic characteristics of HCC remain poorly understood. We aimed to reveal the ubiquitomic characteristics of HCC and provide clinical feature biomarkers of the aggressive HCC that may be used for diagnosis or therapy in the clinic.

Approach and results: The comprehensive proteomic, phosphoproteomic, and ubiquitomic analyses were performed on tumors and adjacent normal liver tissues from 85 patients with HCC. HCCs displayed overexpression of drugable targets CBR1-S151 and CPNE1-S55. COL4A1, LAMC1, and LAMA4 were highly expressed in the disease free survival-poor patients. Phosphoproteomic and ubiquitomic features of HCC revealed cross talk in metabolism and metastasis. Ubiquitomics predicted diverse prognosis and clarified HCC subtype-specific proteomic signatures. Expression of biomarkers TUBA1A, BHMT2, BHMT, and ACY1 exhibited differential ubiquitination levels and displayed high prognostic risk scores, suggesting that targeting these proteins or their modified forms may be beneficial for future clinical treatment. We validated that TUBA1A K370 deubiquitination drove severe HCC and labeled an aggressive subtype of HCCs. TUBA1A K370 deubiquitination was at least partly attributed to protein kinase B-mediated USP14 activation in HCC. Notably, targeting AKT-USP14-TUBA1A complex promoted TUBA1A degradation and blocked liver tumorigenesis in vivo.

Conclusions: This study expands our knowledge of ubiquitomic signatures, biomarkers, and potential therapeutic targets in HCC.

Keywords: phosphoproteomics; prognostic biomarkers; proteomics; ubiquitination; ubiquitomics.

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References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.
    1. Ye Q, Ling S, Zheng S, Xu X. Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA. Molecular Cancer. 2019;18:114.
    1. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.
    1. Wu MZ, Yuan YC, Huang BY, Chen JX, Li BK, Fang JH, et al. Identification of a TGF-beta/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis. Signal Transduct Target Ther. 2021;6:395.
    1. 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.e522.

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