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

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/ß-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.