USP2 Promotes Nasopharyngeal Carcinoma Progression by Activating TRAF2/NF‐κB Signaling and Stabilizing MMP2

ABSTRACT Metastasis remains the primary determinant of poor prognosis in nasopharyngeal carcinoma (NPC). While dysregulated ubiquitination drives cancer progression, the functional contributions of deubiquitinating enzymes (DUBs) to NPC dissemination are poorly defined. Here, we investigated USP2, a DUB implicated in oncogenesis, as a potential regulator of NPC migration and invasion. In our study, bioinformatics analysis of the GEO data set GSE200792 identified USP2 as a metastasis‐associated gene with elevated m 6 A methylation and mRNA levels in metastatic NPC. Validation employed qPCR, Western blot, and immunohistochemistry in clinical samples and NPC cell lines. Functional assays included CCK‐8, flow cytometry, Transwell, wound healing, and mechanistic studies such as cyclohexane chase, co‐immunoprecipitation, ubiquitination assays were performed under USP2 knockdown/overexpression and NF‐κB inhibition. Our results showed that USP2 was significantly upregulated in metastatic NPC tissues and cell lines. USP2 knockdown suppressed proliferation, migration, and invasion, induced apoptosis, and attenuated NF‐κB activation by reducing nuclear p65 and TRAF2/MMP2 expression. Conversely, USP2 overexpression enhanced malignancy, which was reversed by NF‐κB inhibition. Critically, USP2 directly bound MMP2, extended its protein half‐life, and reduced K48‐linked polyubiquitination. In conclusion, USP2 drives NPC migration and invasion by activating TRAF2‐dependent NF‐κB signaling and directly mediating K48‐linked deubiquitination of MMP2, dually enhancing MMP2 expression. Targeting the USP2‐MMP2 axis may offer a novel therapeutic strategy to impede NPC dissemination, addressing an unmet clinical need in advanced disease.