Abstract The deubiquitinating enzyme USP14, which belongs to the ubiquitin-specific protease family, is highly expressed in various malignant tumors. The regulatory mechanisms in tumors are complex and diverse, encompassing a range of cellular processes such as proliferation, apoptosis, inflammation, autophagy, and drug resistance. However, the functional role of USP14 in gastric cancer remains unclear. In the current investigation, a significant upregulation of USP14 expression was observed in gastric cancer, and its overexpression was associated with an unfavorable prognosis among patients. The involvement of USP14 is indispensable for promoting the growth, motility, and infiltration of gastric cancer cells, as revealed by our findings. Further investigations revealed that USP14 interacts with KPNA2 and is responsible for deubiquitinating it by removing ubiquitin. Moreover, the deubiquitylation process mediated by USP14 was found to be critically dependent on the K48 residue of ubiquitin. The knockdown of USP14 significantly suppressed the proliferation, migration, and invasion of gastric cancer cells. This effect was attributed to the regulation of c-MYC nuclear translocation through KPNA2 deubiquitination. The findings underscore the imperative for further evaluation of the potential therapeutic significance of USP14 in gastric cancer.
Li et al. (2025) studied this question.