UBE2M as a bridge spanning neddylation and cell cycle regulation in colorectal adenocarcinoma

Protein neddylation is a post-translational modification process that modifies the functional state of proteins by conjugating NEDD8, a ubiquitin-like polypeptide, to the lysine residues of substrates. In various cancers, neddylation is upregulated and implicated in cancer progression via modulating cell cycle-related proteins. However, in colorectal cancer (CRC), the relationship between neddylation and the cell cycle remains incompletely understood. Here, by leveraging single-cell and bulk transcriptome data, we demonstrated that neddylation is associated with G2M phase progression in CRC. Through bioinformatic analysis, we identified ubiquitin conjugating enzyme E2 M (UBE2M) as a molecular bridge spanning neddylation and the cell cycle in CRC. To elucidate how UBE2M promotes CRC progression, we conducted in vivo and in vitro experiments to confirm the role of UBE2M in neddylating USP39, which in turn modulates the deubiquitination of PABPC1, enhances the translation efficiency of CCNB1 and propels the cell cycle progression of CRC. Regarding clinical application, we identified micafungin as an inhibitor of UBE2M capable of suppressing the regulatory axis and, consequently, hindering CRC progression. Therefore, this study underscores the potential role of UBE2M in bridging neddylation with the cell cycle and holds promise for advancing targeted therapies in CRC treatment.