Galectin-3 promotes FBXL5-dependent ubiquitination and degradation of YAP1 to constrain colorectal cancer growth

IntroductionThe molecular heterogeneity of colorectal cancer (CRC) profoundly shapes clinical outcomes and treatment response, underscoring the need to elucidate the underlying mechanisms to refine diagnosis and therapy. Although LGALS3, which encodes Galectin-3 (Gal-3), has been implicated in tumor biology, its precise role and regulatory mechanism in CRC remain incompletely understood.

This study aimed to define the clinical relevance and mechanistic function of the Gal-3-related signaling axis in CRC.MethodsWe integrated TCGA and single-cell RNA sequencing data to evaluate the clinical significance of LGALS3 in CRC. Molecular investigations, including co-immunoprecipitation and ubiquitination assays, were performed to examine how Gal-3 regulated FBXL5 and YAP1.

Functional effects were further assessed using cell proliferation assays and xenograft mouse models to investigate the biological role of the Gal-3-FBXL5-YAP1 axis.ResultsGal-3 positively correlated with FBXL5 and bound FBXL5 to enhance its expression. Patients with high LGALS3 and FBXL5 expression exhibited better survival.

Mechanistically, FBXL5 promoted YAP1 protein degradation through the ubiquitin pathway without altering YAP1 transcript levels, suggesting a post-transcriptional regulatory mechanism.