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Abstract Objective USP14 (Ubiquitin‐specific‐processing protease 14) is a deubiquitinating enzyme with oncogenic effects in oral squamous cell carcinoma (OSCC). This study aims to identify new substrates of USP14 and elucidate their role in modulating cancer stem‐like cells (CSCs) in OSCC. Materials and Methods Bioinformatics prediction and docking were performed using UbiBrowser 2.0 and HDOCK, respectively. OSCC cell lines and patient‐derived cells were used for experimental validation, employing co‐immunoprecipitation, cycloheximide chase assays, and tumor sphere formation to evaluate the effects of USP14 on SOX2 stability, ubiquitination, and CSC phenotypes. Results USP14 upregulation was associated with worse overall survival and progression‐free interval in OSCC. USP14 interacted with SOX2 with its ubiquitin carboxyl‐terminal hydrolase domain. USP14 knockdown impaired SOX2 stability by increasing its polyubiquitination. Ectopic overexpression of wild‐type USP14, but not the hydrolase‐deficient‐mutant USP14 C114A , enhanced SOX2 stability by reducing polyubiquitination. USP14 knockdown suppressed OSCC cell proliferation, colony formation, and tumor sphere formation in vitro and tumor growth in vivo. However, the reduction of CSC markers following USP14 knockdown was mitigated by overexpressing SOX2 . These findings were verified in OSCC patient‐derived CSC cells. Conclusion This study revealed a USP14‐SOX2 axis regulating the CSC properties of OSCC.
Liu et al. (Tue,) studied this question.