TRIM39 aggravates hepatocellular carcinoma growth through targeting the p62-KEAP1-NRF2 axis

The tripartite motif (TRIM) protein family plays important roles in the initiation and progression of various tumors through different mechanisms. However, the biological functions of TRIM39 and its underlying mechanism in hepatocellular carcinoma (HCC) remain largely unknown. In this study, we found that the expression of TRIM39 was increased in HCC tissues compared to adjacent normal tissues and negatively correlated with the prognosis of HCC patients. Functional studies demonstrated that TRIM39 promoted the proliferation of HCC cells in vitro and in vivo. Mechanistically, TRIM39 interacted with p62 and facilitated its ubiquitination, leading to a decrease of p62 protein stability. The downregulation of p62 released KEAP1, which subsequently inhibited NRF2-HO-1 pathway. Moreover, overexpression p62 counteracted the pro-tumor phenotypes induced by TRIM39 in HCC. In conclusion, our study elucidates the oncogenic roles and the relevant mechanisms of TRIM39 in HCC, highlights the TRIM39-p62-Keap1-NRF2 axis in HCC progression. These findings may provide potential therapeutic targets for HCC treatment.