Ubiquitin-conjugating enzyme E2 J1 (UBE2J1) has been shown to be involved in the ubiquitination of various substrate proteins; however, its mechanistic role in cancer initiation and progression remains poorly understood. In this study, we demonstrate that UBE2J1 expression is significantly reduced in colorectal cancer (CRC) tissues and cell lines as a consequence of promoter DNA hypermethylation, and that low UBE2J1 levels are correlated with unfavorable clinical outcomes. Functional analyses reveal that UBE2J1 acts as a tumor suppressor, markedly inhibiting CRC cell proliferation and metastatic potential. Mechanistically, UBE2J1 forms an E2–E3 ubiquitination complex with TRIM25, which directly interacts with ribosomal protein S3 (RPS3) and promotes its ubiquitination and proteasomal degradation at lysine 214. The resulting reduction in RPS3 levels impairs nuclear translocation of NF-κB, thereby suppressing activation of the NF-κB signaling pathway. Collectively, our findings uncover a previously unrecognized mechanism whereby UBE2J1-mediated polyubiquitination and degradation of RPS3 disrupts NF-κB signaling, highlighting UBE2J1 as a potential prognostic biomarker and therapeutic target in CRC.
