Abstract
Ubiquitin-conjugating enzyme E2 J1 (UBE2J1) has been proven to participate in the ubiquitination of multiple substrate proteins. However, the underlying mechanisms of UBE2J1 as a ubiquitin-conjugating enzyme participating in cancer development and progression remain largely unknown. Here, we identified that UBE2J1 is downregulated in colorectal cancer (CRC) tissues and cell lines which are mediated by DNA hypermethylation of its promoter, and decreased UBE2J1 is associated with poor prognosis. Functionally, UBE2J1 serving as a suppressor gene inhibits the proliferation and metastasis of CRC cells. Mechanistically, UBE2J1-TRIM25, forming an E2-E3 complex, physically interacts with and targets RPS3 for ubiquitination and degradation at the K214 residue. The downregulated RPS3 caused by UBE2J1 overexpression restrains NF-κB translocation into the nucleus and therefore inactivates the NF-κB signaling pathway. Our study revealed a novel role of UBE2J1-mediated RPS3 poly-ubiquitination and degradation in disrupting the NF-κB signaling pathway, which may serve as a novel and promising biomarker and therapeutic target for CRC.