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

Abstract

Abstract In a previous study, we discovered that the lnc-TSPAN12 level was significantly elevated in hepatocellular carcinoma (HCC) and linked to a low chance of survival. In HCC, however, the function of lnc-TSPAN12 in modulating epithelial-mesenchymal transition (EMT) and metastasis is still poorly understood. This study demonstrated that lnc-TSPAN12 positively modulated migration, invasion, and EMT of HCC cells in vitro and exacerbated hepatic metastasis in patient-derived tumour xenograft metastatic models in vivo. The modification of N6-methyladenosine that is driven by METTL3 is essential because it is involved in the upregulation of lnc-TSPAN12, which contributes to the stability of lnc-TSPAN12. Mechanistically, lnc-TSPAN12 exhibits direct physical interactions with EIF3I and SENP1, and it also assumes the role of a scaffold to help enhance the SENP1-EIF3I interaction. This in turn inhibits the SUMOylation of EIF3I and the degradation of ubiquitin, eventually activating the Wnt/β-catenin signalling pathway to stimulate EMT and metastasis of HCC. Our results shed light on the lnc-TSPAN12 regulation mechanism in HCC metastasis and identify the lnc-TSPAN12-EIF3I/SENP1 axis as a novel treatment target for HCC.