The dysregulation of deubiquitinating enzymes has been reported to be important in the development of many human cancers, including pancreatic cancer. However, the precise role and potential mechanism of action of the deubiquitinating enzyme UCHL3 in pancreatic cancer progression and chemo-resistance, are poorly elucidated. In the current study, the consequences of UCHL3 knockdown in pancreatic cancer cells were evaluated via cell viability and colony formation assays. experiments were also conducted to confirm the effect of UCHL3 and FOXM1 depletion on tumor growth in nude mouse xenograft models. Cell migration and invasion were assessed by wound-healing and transwell assays, respectively. Co-immunoprecipitation (co-IP) and deubiquitination assays were performed to investigate the interactions between UCHL3 and FOXM1. Immunohistochemical (IHC) staining was utilized to examine the expression of UCHL3 and FOXM1 in pancreatic cancer tissues. Our results demonstrate that UCHL3 deubiquitinated and stabilized FOXM1, thereby potentiating proliferation, migration, and invasion of pancreatic cancer cells. Furthermore, knockdown of UCHL3 increased FOXM1 ubiquitination, which enhanced FOXM1 turnover and promoted pancreatic cancer cells' sensitivity to gemcitabine. High UCHL3 expression was positively associated with FOXM1 expression level in pancreatic cancer patient samples. Collectively, our study established the UCHL3-FOXM1 axis as a pivotal driver of pancreatic cancer progression and gemcitabine resistance and provided evidence for the potential therapeutic benefit of targeting the UCHL3-FOXM1 axis for pancreatic cancer treatment.
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