USP18 orchestrates malignant progression in nasopharyngeal carcinoma through UBR5-driven attenuation of p53 signaling

BACKGROUND: Ubiquitin-specific protease 18 (USP18) is a deubiquitinating enzyme initially recognized for its regulatory role in interferon signaling and antiviral immunity. In recent years, aberrant overexpression of USP18 has been increasingly reported across various malignancies, where it is implicated in tumor proliferation and immune evasion. However, its expression profile and mechanistic function in nasopharyngeal carcinoma (NPC) remain largely uncharacterized. METHODS: This study systematically assessed USP18 expression and its clinical relevance in NPC by integrating analyses of public databases with evaluation of clinical tissue specimens. Functional characterization was performed using NPC cell lines engineered for USP18 overexpression or silencing, followed by assays measuring cell proliferation, migration, invasion, apoptosis, and cell cycle dynamics. In vivo validation was conducted via subcutaneous xenograft models in nude mice. Mechanistic insights were further obtained through transcriptomic profiling (RNA-seq) and proteomic analysis of USP18-interacting proteins, leading to the identification of downstream targets and signaling pathways. Rescue experiments were employed to delineate the regulatory network orchestrated by USP18 in NPC. RESULTS: USP18 was markedly upregulated in NPC tissues and its elevated expression correlated with poor clinical prognosis. Gain- and loss-of-function experiments demonstrated that USP18 significantly enhanced NPC cell proliferation, migration, and invasion, while concurrently suppressing apoptosis. Mechanistically, USP18 was found to interact with the E3 ubiquitin ligase UBR5, thereby attenuating activation of the canonical tumor suppressor pathway p53, resulting in downregulation of its downstream effectors involved in apoptosis and cell cycle arrest. Co-immunoprecipitation assays further validated the physical interaction between USP18 and UBR5, suggesting that USP18 may regulate p53 signaling through UBR5-mediated mechanisms. CONCLUSIONS: This study unveils a previously unrecognized oncogenic mechanism wherein USP18 promotes malignant progression of nasopharyngeal carcinoma via UBR5-dependent suppression of the p53 signaling pathway. These findings highlight USP18 as a promising candidate biomarker and potential therapeutic target in NPC.