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METTL3-mediated m6A modification of lncRNA TSPAN12 promotes metastasis of hepatocellular carcinoma through SENP1-depentent deSUMOylation of EIF3I

Oncogene volume 43, pages 1050–1062 (2024)Cite this article

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Abstract

In a previous study, we discovered that the level of lnc-TSPAN12 was significantly elevated in hepatocellular carcinoma (HCC) and correlated with a low survival rate. However, the function and mechanism of lnc-TSPAN12 in modulating epithelial-mesenchymal transition (EMT) and metastasis in HCC remains poorly understood. This study demonstrates that lnc-TSPAN12 positively influences migration, invasion, and EMT of HCC cells in vitro and promotes hepatic metastasis in vivo. The modification of N6-methyladenosine, driven by METTL3, is essential for the stability of lnc-TSPAN12, which may partially contribute to the upregulation of lnc-TSPAN12. Mechanistically, lnc-TSPAN12 exhibits direct interactions with EIF3I and SENP1, acting as a scaffold to enhance the SENP1-EIF3I interaction. As a result, the SUMOylation of EIF3I is inhibited, preventing its ubiquitin-mediated degradation. Ultimately, this activates the Wnt/β-catenin signaling pathway, stimulating EMT and metastasis in HCC. Our findings shed light on the regulatory mechanism of lnc-TSPAN12 in HCC metastasis and identify the lnc-TSPAN12-EIF3I/SENP1 axis as a novel therapeutic target for HCC.

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Fig. 1: Lnc-TSPAN12 promotes migration, invasion and EMT of HCC cells in vitro.
Fig. 2: Lnc-TSPAN12 promotes metastasis in HCC.
Fig. 3: Lnc-TSPAN12 physically interacts with EIF3I and SENP1.
Fig. 4: Lnc-TSPAN12 enhances the stability of EIF3I protein by blocking its ubiquitination degradation.
Fig. 5: Lnc-TSPAN12 knockdown promotes EIF3I ubiquitination through suppressing SENP1-mediated deSUMOylation.
Fig. 6: Lnc-TSPAN12 exerts EMT-promoting functions in HCC by regulating EIF3I/SENP1.
Fig. 7: Lnc-TSPAN12 is upregulated in HCC through METTL3-mediated m6A modification.
Fig. 8

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Data availability

The data in this study are available upon request from the corresponding author.

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Funding

This work as supported by the National Natural Science Foundation of China (No. 82002578), 1·3·5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (No. 20HXFH021), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (No. ZYJC21049).

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Authors and Affiliations

  1. Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Bei Li, Xianze Xiong, Guilin Nie, Ningyuan Wen, Yaoqun Wang & Jiong Lu

  2. Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Bei Li, Jianrong Xu, Dingzhong Peng, Ningyuan Wen, Yaoqun Wang & Jiong Lu

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Contributions

J.L. and X.X. considered and designed the study. B.L., J.X., D.P. and G.N. performed experiments. B.L., X.X., N.W. and Y.W. did data analyses. J.L. and B.L. wrote the manuscript. J.L., B.L. and X. X contributed to the revision of manuscript. All authors read and approved the final manuscript.

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Correspondence to Jiong Lu.

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All animal experiments involved in this study were performed in conformity to the National Institutes of Health Guide for the Care and Use of Laboratory Animals following approval by the Laboratory Animal Ethnics Committees of West China Hospital of Sichuan University (approval number: 20220926005).

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Li, B., Xiong, X., Xu, J. et al. METTL3-mediated m6A modification of lncRNA TSPAN12 promotes metastasis of hepatocellular carcinoma through SENP1-depentent deSUMOylation of EIF3I. Oncogene 43, 1050–1062 (2024). https://doi.org/10.1038/s41388-024-02970-0

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