NSUN5 facilitates the progression of hepatocellular carcinoma by increasing the expression of SMAD3

Abstract

Abstract Hepatocellular carcinoma (HCC), the most prevalent liver cancer, makes patients' prognosis extremely poor due to frequent intrahepatic and distant metastasis. The epithelial-mesenchymal transition (EMT) plays an important role in this process. However, the content of NSUN5 in hepatocellular carcinoma and whether NSUN5 is involved in mediating the epithelial-mesenchymal transition of hepatocellular carcinoma remains unknown. In this study, based on clinicopathologic analyses of several independent HCC cohorts and the results of induced tumor formation in Nsun5 knockout mice, we observed that NSUN5 expression was increased in tumor tissues. The absence of Nsun5 would retard the malignant progression of hepatocellular carcinoma, suggesting that Nsun5 might be an important oncogene in HCC. Furthermore, we found that high expression of NSUN5 promotes EMT in HCC cells. After NSUN5 is knocked out, the HCC cell's ability to invade and migrate decreases in vivo and vitro conditions; on the other hand, NSUN5 overexpression in HCC cells had the opposite effect. Mechanically, the highly expressed NSUN5 in cancer tissues promotes the enrichment of Tri-Methyl-histone H3 (Lys4) in the promoter region of SMAD3 by interacting with WDR5, thereby promoting hepatocellular carcinoma metastasis by SMADd3-mediated EMT. In general, we identified NSUN5 as a novel promoter of metastasis in hepatocellular carcinoma and established an innovative theoretical foundation for treating this disease.