SND1 promotes colorectal cancer progression and metastasis by stabilizing HK2 through the inhibition of FBW7-mediated ubiquitination

BACKGROUND: Metabolic reprogramming, particularly enhanced aerobic glycolysis, is a hallmark of colorectal cancer (CRC) progression and metastasis. However, the key regulatory mechanisms linking glycolytic remodeling to metastatic progression remain incompletely understood. METHODS: We integrated single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk transcriptomic analyses, and machine-learning approaches to identify glycolysis-associated drivers in CRC. Clinical relevance was validated in patient samples by qRT-PCR, western blotting, immunohistochemistry, and survival analyses. Gain- and loss-of-function experiments were performed to investigate the biological role of SND1 in CRC cells. Metabolic alterations were assessed using Seahorse flux analysis, glucose uptake, and lactate production assays. Co-immunoprecipitation, cycloheximide chase, and ubiquitination assays were conducted to explore the underlying mechanism. Subcutaneous xenograft and tail-vein metastasis models were used to evaluate the in vivo effects of SND1. RESULTS: Single-cell analysis revealed glycolytic heterogeneity within the CRC microenvironment. Metastatic malignant epithelial cells showed higher cell-level glycolysis-score distributions, whereas patient-paired and mixed-effects comparisons did not reach statistical significance. Integrative multi-omics and machine-learning analyses prioritized SND1 as a glycolysis-associated candidate for subsequent functional investigation. SND1 was significantly upregulated in CRC tissues, and high SND1 expression was associated with poorer overall and disease-free survival after adjustment for TNM stage. Functionally, SND1 promoted CRC cell proliferation, colony formation, migration, invasion, and EMT-like phenotypes. In addition, SND1 enhanced glycolytic reprogramming, as evidenced by increased glucose uptake, lactate production, and extracellular acidification rate. Mechanistically, SND1 directly interacted with HK2 and stabilized HK2 protein by suppressing its ubiquitin-mediated proteasomal degradation. Further analyses showed that SND1 antagonized FBW7-mediated ubiquitination of HK2, whereas restoration of HK2 partially rescued the impaired malignant phenotypes caused by SND1 depletion. In vivo, SND1 silencing markedly inhibited tumor growth and pulmonary metastatic colonization. CONCLUSIONS: SND1 is a glycolysis-associated oncogenic driver in CRC that promotes tumor progression and metastasis, at least in part, by stabilizing HK2 through inhibition of FBW7-mediated ubiquitination. Targeting the SND1/FBW7/HK2 axis may provide a potential therapeutic strategy for CRC.