RNF149 Promotes HCC Progression through Its E3 Ubiquitin Ligase Activity

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) accounts for over 80% of cases among liver cancer, with high incidence and poor prognosis. Thus, it is of valuable clinical significance for discovery of potential biomarkers and drug targets for HCC. In this study, based on proteomics data analysis, really interesting new gene (RING) finger protein 149 (RNF149) was found to be elevated in hepatocellular carcinoma (HCC) tissues and associated with HCC malignancy, which was validated by immunohistochemistry (IHC) staining. RNF149 was demonstrated to promote proliferation, migration, and invasion of HCC cells dependent on its E3 ubiquitin ligase activity in vitro, and further bioinformatics analysis indicated that high expression of RNF149 correlated with immunosuppressive tumor microenvironment (TME). These results suggest that RNF149 could exert protumor functions in HCC in dependence of its E3 ubiquitin ligase activity, and might be a potential prognostic marker and therapeutic target for HCC treatment. ABSTRACT: Hepatocellular carcinoma (HCC) accounts for over 80% of cases among liver cancer, with high incidence and poor prognosis. Thus, it is of valuable clinical significance for discovery of potential biomarkers and drug targets for HCC. In this study, based on the proteomic profiling data of paired early-stage HCC samples, we found that RNF149 was strikingly upregulated in tumor tissues and correlated with poor prognosis in HCC patients, which was further validated by IHC staining experiments of an independent HCC cohort. Consistently, overexpression of RNF149 significantly promoted cell proliferation, migration, and invasion of HCC cells. We further proved that RNF149 stimulated HCC progression via its E3 ubiquitin ligase activity, and identified DNAJC25 as its new substrate. In addition, bioinformatics analysis showed that high expression of RNF149 was correlated with immunosuppressive tumor microenvironment (TME), indicating its potential role in immune regulation of HCC. These results suggest that RNF149 could exert protumor functions in HCC in dependence of its E3 ubiquitin ligase activity, and might be a potential prognostic marker and therapeutic target for HCC treatment.