Ubiquitin C-terminal hydrolase L3 promotes liver cancer cell proliferation by modulating the AMP-activated protein kinase signaling pathway

The deubiquitinase Ubiquitin C-Terminal Hydrolase L3 (UCHL3) is highly expressed in multiple cancer types and generally considered as an oncogene. However, its functions in liver cancer are unclear. This study investigated the role of UCHL3 in liver cancer cell growth and evaluated its potential clinical significance as a prognostic marker. The expression of UCHL3 in cancer and its correlations with clinical parameters were assessed by using TCGA databases. Gene expression was analyzed by real time-PCR, Western Blotting, and immunostaining. Colony formation assays were performed and growth curve were measured to evaluate the function of UCHL3 in liver cancer cell proliferation. Gene Set Enrichment Analysis (GSEA) was used to explore enriched pathways. We found that UCHL3 was essential in promoting liver cancer cell proliferation. It was highly expressed in liver cancer tissues and was a negative prognostic marker for liver cancer. Knocking down UCHL3 reduced the expression of cell cycle regulators, such as Cyclin A2, Cyclin B1 and MAD2, inhibiting cell cycle progression. The inhibition was partially due to the alteration of autophagy upon UCHL3 deprivation, as disruption of autophagy restored the protein level of Cyclin B1 and reversed cell cycle arrest. Suppressing UCHL3 was associated with the activation of AMP-activated protein kinase (AMPK) signaling pathway, which was important in controlling autophagy activation. UCHL3 may negatively modulate the AMPK pathway and autophagy in liver cancer to maintain the expression of cell cycle regulators and facilitate cell proliferation. Targeting overexpressed UCHL3 may be feasible to inhibit liver cancer progression.