UCHL1 acts as a colorectal cancer oncogene via activation of the β-catenin/TCF pathway through its deubiquitinating activity.

Ubiquitin C-terminal hydrolase-L1 (UCHL1) belongs to the family of deubiquitinating enzymes (DUBs), which is involved in the ubiquitin-dependent proteolytic system. Previously, we have reported that the upregulation of UCHL1 is related to lymph node metastasis in colorectal cancer (CRC). However, its molecular mechanisms remain elusive. In this study, we transfected pcDNA3.1/UCHL1 and the pcDNA3.1/UCHL1-C90S mutant into HCT8 cells. The changes in biological features in these stable transfectants were examined both in vitro and in vivo. Western blot analysis was used to analyze the changes in the β-catenin/T cell factor (TCF) pathway. We demonstrated that UCHL1 re-expression promoted the proliferation, migration and metastasis potential of HCT8 cells both in vitro and in vivo. We also found that UCHL1 could decelerate β-catenin degradation depending on its deubiquitinating activity. The accumulated β-catenin consequently activated the β-catenin/TCF pathway and induced the expression of cyclin D1 and uPA. These observations imply that UCHL1 may contribute to CRC progression by activating the β-catenin/TCF pathway through its deubi-quitinating activity.