Oncogenic SOX9-TRAIP signaling drives gastric cancer progression by mediating the degradation of the CPEB3-mTORC1 tumor suppressor axis.

backgroundGastric cancer (GC) is a leading cause of cancer mortality worldwide, driven by complex and heterogeneous molecular alterations. The ubiquitin-proteasome system, particularly E3 ubiquitin ligases, is frequently dysregulated in cancer, yet its key players in GC remain incompletely defined. This study aimed to identify novel oncogenic E3 ligases in GC and to elucidate their molecular mechanisms.

methodsWe performed a systematic multi-cohort transcriptomic analysis of public datasets (GEO, TCGA) to screen for and validate key E3 ubiquitin ligases. The oncogenic functions were validated using shRNA-mediated knockdown, overexpression, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), ubiquitylation assays, luciferase reporter assays, and a series of cell-based functional assays (proliferation, colony formation, invasion), as well as a subcutaneous xenograft model in nude mice.

resultsWe identified TRAF-interacting protein (TRAIP), an E3 ubiquitin ligase, as a critically overexpressed gene in GC that strongly correlates with poor patient prognosis. We delineated a complete and linear signaling cascade, demonstrating that the oncogenic transcription factor SOX9 directly binds to the TRAIP promoter and drives its transcriptional upregulation. Mechanistically, TRAIP functions as the specific E3 ligase for the RNA-binding protein and tumor suppressor, CPEB3, mediating its poly-ubiquitylation and subsequent proteasomal degradation. This TRAIP-mediated destruction of CPEB3 relieves its translational repression of key oncogenic targets, leading to the hyperactivation of the mTORC1 signaling pathway. Functionally, TRAIP is indispensable for GC cell proliferation, invasion, and in vivo tumorigenicity. Epistatic rescue experiments revealed that the oncogenic effects of TRAIP are almost entirely dependent on its ability to degrade CPEB3.

conclusionOur findings define the SOX9-TRAIP-CPEB3-mTORC1 axis as a central, hierarchical signaling network driving GC progression. This work not only uncovers a novel oncogenic cascade but also provides a compelling mechanistic rationale for exploring the therapeutic potential of targeting this axis for therapeutic intervention.