UCHL3 inhibits ferroptosis by stabilizing -catenin and maintains stem-like properties of hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic liver cancer. Dysregulated Wnt/beta-catenin activation is closely related to the progression of cancer. Nevertheless, the mechanism that sustains the abnormal expression of beta-catenin in HCC has yet to be identified. In this study, we find that UCHL3 is overexpressed in HCC tissues and correlated with beta-catenin protein level. High expression of UCHL3 is associated with poor prognosis. UCHL3 knockdown markedly reduces the protein level of beta-catenin in HCC cells. TOP-luciferase activity and beta-catenin target genes expression are also decreased upon UCHL3 depletion. We find that the ARM domain of beta-catenin is required for the interaction with UCHL3. UCHL3 increases beta-catenin protein stability via removing K48-specific poly-ubiquitin chains from beta-catenin protein. Furthermore, the depletion of UCHL3 induces ferroptosis and hinders the growth, invasion, and stem cell properties of HCC cells. These impacts could be restored by the overexpression of beta-catenin. In addition, the UCHL3 inhibitor TCID inhibits the aggressive phenotype of HCC through the degradation of beta-catenin. In general, our results indicates that UCHL3 increases the stability of beta-catenin, which in turn facilitates tumorigenesis of HCC, suggesting that targeting UCHL3 may be a promising approach for the treatment of HCC.