SENP1-mediated deSUMOylation of YBX1 promotes colorectal cancer development through the SENP1-YBX1-AKT signaling axis

Aberrant SUMOylation is associated with the progression of colorectal cancer (CRC). The SUMO-specific protease 1 (SENP1)-induced deSUMOylation of different target substrates plays specific roles in CRC. In this study, we dissected the SENP1-interacting protein complex by employing protein co-immunoprecipitation enrichment in combination with His₆-SUMO1^T95K-tagging mass spectrometry (MS) identification, and identified YBX1 as a novel substrate of SENP1. Further studies revealed that SENP1 interacted with YBX1 and consequently catalyzed YBX1 deSUMOylation at K26 residue preferentially. SENP1-mediated deSUMOylation enhanced the pro-tumor activity of YBX1 protein by maintaining the interaction of YBX1 with DDX5, thereby activating AKT phosphorylation signaling and promoting CRC tumor growth. Indeed, SENP1 knockdown elevated YBX1 SUMOylation and disrupted the interaction between YBX1 with DDX5, which significantly inhibited CRC cell proliferation and migration. And overexpression of K26 mutant YBX1 (YBX1-K26R) protein rescued the anti-tumor effect of SENP1 depletion compared with the wild-type YBX1 (YBX1-WT). Moreover, the expression levels of SENP1 and YBX1 were both increased in CRC specimens and associated with poor outcomes in CRC patients. In general, our studies have revealed SENP1-mediated YBX1 protein deSUMOylation promotes CRC progression through the activation of AKT phosphorylation signaling, suggesting that targeting the SENP1-YBX1-AKT signaling axis is a promising therapeutic strategy for CRC.