UBE2B Drives NF-κB Signaling and Gastric Cancer Progression through BIRC2-Mediated K63-Linked Ubiquitination of TRAF1

Ubiquitin-conjugating enzymes (E2s) are essential mediators of ubiquitin-dependent signaling cascades, governing diverse cellular processes such as proteolysis and transcriptional regulation. Despite increasing evidence linking E2 enzymes to tumorigenesis, their precise roles in gastric cancer (GC) remain incompletely defined. Here, we identified UBE2B as a key oncogenic E2 enzyme significantly upregulated in GC tissues through integrative bioinformatics analysis and clinical validation. High UBE2B expression was associated with poor patient prognosis and aggressive clinicopathological features. Functional assays demonstrated that UBE2B promotes GC cell proliferation both in vitro and in vivo. Mechanistically, UBE2B interacts with the E3 ligase BIRC2 to catalyze K63-linked ubiquitination of TRAF1, thereby amplifying NF-κB signaling. Furthermore, chromatin immunoprecipitation and luciferase reporter assays revealed that NF-κB subunit P65 directly binds to the UBE2B promoter, enhancing its transcription and forming a feedforward regulatory loop. This UBE2B–BIRC2–TRAF1 axis, coupled with the UBE2B–TRAF1–P65 feedback circuitry, establishes a self-sustaining mechanism that drives NF-κB hyperactivation and tumor cell proliferation. Collectively, our findings highlight UBE2B as a critical modulator of GC progression and a potential target for therapeutic intervention. Implications: This study characterizes the UBE2B–BIRC2–TRAF1 axis as a driver of NF-κB hyperactivation, identifying UBE2B as a prognostic biomarker and a potential therapeutic target for disrupting this oncogenic feedback loop in gastric cancer.