ML-792

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.

Glucocorticoids are a mainstay in the treatment of B-cell acute lymphoblastic leukemia (B-ALL). The glucocorticoid receptor (GR), a ligand-activated transcription factor (TF), mediates their actions. Chromatin occupancy, chromatin-protein networks (chromatomes) and gene programmes of GR are regulated by SUMOylation, a post-translational modification with therapeutic implications in other hematomalignancies. To unravel the GR-SUMOylation crosstalk in B-ALL, we induced hypoSUMOylation in NALM6 B-ALL cells with a SUMOylation inhibitor (SUMOi, ML-792). Genome-wide profiling of GR and SUMO chromatin-binding and chromatin accessibility revealed that hypoSUMOylation augmented GR chromatin occupancy and altered chromatin openness. Association with transcriptome data indicated that the hypoSUMOylation-induced GR-binding sites predominantly repressed genes associated with cell cycle and DNA replication. Consistently, hypoSUMOylation potentiated glucocorticoid-induced cell cycle arrest and growth suppression. Moreover, our proteomic analyses revealed that the protein network of chromatin-bound GR is tightly intertwined with SUMO2/3 and that SUMOylation modulates the stability of the network. The chromatome contained several B-cell TFs with cognate binding motifs found on GR-adjacent chromatin sites, indicating their simultaneous occupancy on chromatin. In sum, our data imply potential for targeting SUMOylation to increase sensitivity to glucocorticoids in B-ALL, supported by ex vivo data of glucocorticoid and SUMOi TAK-981 combination-treated B-ALL patient samples.