Abstract
Background: CPEB4, an RNA-binding protein that regulates the translational efficiency of target genes, has been implicated in playing dual roles in tumor progression across multiple cancer types. This study aims to investigate the role of CPEB4 in head and neck squamous cell carcinoma (HNSCC), particularly focusing on nasopharyngeal carcinoma. Methods: Differentially expressed proteins associated with CPEB4 were identified using iTRAQ-based proteomics. Consensus clustering stratified 495 HNSCC cases into two distinct molecular subtypes (C1 and C2). A prognostic risk model was constructed using LASSO regression. The effects of CPEB4 on cellular invasion and migration were analyzed in NPC cells. Western blotting assessed PI3K/AKT and WNT/β-catenin pathways and EMT markers. β-catenin nuclear activity was analyzed by immunofluorescence and western blot. A nude mouse xenograft model validated the CPEB4/β-catenin axis. Results: A total of 731 proteins were identified as differentially expressed. The C2 molecular subtype exhibited significantly worse prognosis, higher tumor stemness indices, and greater sensitivity to six commonly used chemotherapeutic agents compared to C1. Overexpression of CPEB4 in NPC cells enhanced invasion and migration. Mechanistically, CPEB4 upregulated β-catenin expression and nuclear activity by targeting CPE elements within the CTNNB1 mRNA, which were inhibited by β-catenin inhibitors. In vivo experiments confirmed that CPEB4 overexpression promoted tumor invasiveness and migration, effects that were effectively suppressed by β-catenin inhibitors. Conclusions: CPEB4 overexpression drives tumor progression in NPC by translationally upregulating β-catenin, thereby promoting cell invasion and migration. The poor prognosis associated with CPEB4 is linked to enhanced tumor aggressiveness. Importantly, β-catenin inhibitors effectively counteract the pro-invasive and pro-migratory effects mediated by CPEB4, underscoring their potential as therapeutic agents in CPEB4-overexpressing tumors.