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USP11 potentiates HGF/AKT signaling and drives metastasis in hepatocellular carcinoma

Oncogene volume 43, pages 123–135 (2024)Cite this article

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Abstract

USP11 is a member of the ubiquitin-specific protease family and plays a crucial role in tumor progression in various cancers. However, the precise mechanism by which USP11 promotes EMT and metastasis in hepatocellular carcinoma (HCC) is not fully understood. In this study, we demonstrated that the USP11 expression was dramatically upregulated in HCC tissues and cell lines. Increased USP11 expression was closely associated with tumor number, vascular invasion, and poor prognosis. Functional experiments demonstrated that USP11 markedly promoted metastasis and EMT in HCC via induction of the transcription factor Snail. Mechanistically, USP11 interacted with and deubiquitinated eEF1A1 on Lys439, thereby inhibiting its ubiquitin-mediated degradation. Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription. This led to an enhanced expression of HGF and the activation of the downstream PI3K/AKT signaling pathway. We demonstrated that USP11 promotes EMT and metastasis in HCC via eEF1A1/SP1/HGF dependent-EMT. Our findings suggest that the USP11/ eEF1A1/SP1/HGF axis contributes to metastasis in HCC, and therefore, could be considered as a potential therapeutic target for the treatment of HCC.

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Fig. 1: USP11 is upregulated in HCC and correlates with poor prognosis.
Fig. 2: USP11 promotes HCC EMT and metastasis.
Fig. 3: USP11 interacts with eEF1A1 and increases its expression depend on its deubiquitinase activity.
Fig. 4: UPS11 stabilizes and deubiquitinates eEF1A1 on Lys439.
Fig. 5: RNA Sequence Identifies HGF as Downstream effector of eEF1A1.
Fig. 6: eEF1A1 interacts with SP1 to activate HGF/AKT signaling.
Fig. 7: eEF1A1 mediates USP11-induced metastasis and EMT.

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Data availability

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank SpecAlly Life Technology Co., Ltd for proteomic expertise.

Funding

This work was supported by The National Natural Science Foundation of China (NO.82003003 to JC, No.81874189 to BZ, NO.81472705 to LJ), State Key Project on Infection Disease of China (No. 2018ZX10723204-003) and Projects of Natural Science Foundation of Hubei Province (Grant No. 2021CFB391 to LJ).

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  1. These authors contributed equally: Jin Chen, Deng Ning.

Authors and Affiliations

  1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei, 430030, PR China

    Jin Chen, Deng Ning, Qiumeng Liu, Jie Mo, Huifang Liang, Wanguang Zhang, Bixiang Zhang & Xiaoping Chen

  2. Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China

    Deng Ning

  3. Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China

    Pengcheng Du & Li Jiang

  4. Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Mingzhi Zhang

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Contributions

CXP, ZBX, and JL conceived and designed the project. JC, ND, and DPC performed the experiments. LQM and MJ collected the clinical specimens and data. LHF performed the statistical analysis. CJ and ND drafted the manuscript. ZXW, ZWG, and ZMZ contributed to critical revision of the paper. All authors read and approved the final manuscript.

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Correspondence to Li Jiang, Bixiang Zhang or Xiaoping Chen.

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Chen, J., Ning, D., Du, P. et al. USP11 potentiates HGF/AKT signaling and drives metastasis in hepatocellular carcinoma. Oncogene 43, 123–135 (2024). https://doi.org/10.1038/s41388-023-02847-8

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