Deubiquitinase OTUB2 promotes intrahepatic cholangiocarcinoma progression by stabilizing the CTNNB1-ZEB1 axis

Aberrant regulation of ubiquitination is an essential fundamental process in tumors, especially intrahepatic cholangiocarcinoma (iCCA). We reported that OTUB2, an OTU deubiquitinase, is upregulated in iCCA and stabilizes the CTNNB1-ZEB1 axis, resulting in epithelial-mesenchymal transition (EMT) and iCCA metastasis. Mechanistically, OTUB2 promotes CTNNB1 expression by interacting with the E3 ligase TRAF6. OTUB2 inhibits the lysosomal degradation of CTNNB1 by interacting with TRAF6 and thus regulates the progression of iCCA through ZEB1. Clinically, high OTUB2 expression is related to increased ZEB1 expression and activity and reduced overall survival in iCCA patients. Therefore, advanced iCCA patients may benefit from drugs targeting OTUB2 and its pathway.