Role of Kcash2 and Hedgehog signaling pathway in Inflammatory Bowel Disease-associated to Colorectal Cancer

The Hedgehog (Hh) pathway regulates intestinal stem cell renewal and differentiation, and its dysregulation contributes to several cancers, including inflammatory bowel disease (IBD)-related colorectal cancer (CRC). Among its inhibitors, KCASH2 acts as a tumor suppressor by promoting HDAC1 degradation, maintaining Gli1 acetylation, and repressing Hh signaling. In silico analyses of ulcerative colitis-associated CRC patients revealed reduced KCASH2 expression and an inverse correlation with Gli1, suggesting a role for KCASH2 in disease progression. Using a KCASH2-KO mouse model combined with AOM/DSS treatment, we demonstrate that KCASH2 loss increases susceptibility to DSS-induced injury, as evidenced by higher mortality, severe weight loss, colon shortening, impaired epithelial recovery and diffuse immune cells infiltration. Consistently, KCASH2 deficiency was associated with enhanced NF-κB activation, impaired apoptotic clearance of damaged cells, and downregulation of epithelial and tight junction markers. In vitro, KCASH2-silenced HT29 cells showed delayed wound closure under both basal and inflammatory conditions, confirming its role in epithelial regeneration. At tumorigenic stages, KCASH2-KO mice developed more numerous, larger and highergrade dysplastic lesions than WT. Molecular analyses revealed Hh pathway hyperactivation, together with aberrant Wnt/β-catenin and Notch signaling and reduced ERK phosphorylation, indicating oncogenic network reprogramming. In conclusion, KCASH2 loss exacerbates inflammation, impairs epithelial repair, and promotes oncogenic signaling crosstalk, thereby accelerating IBD-related CRC. These findings identify KCASH2 as a key regulator of colonic homeostasis and a potential therapeutic target for inflammationdriven tumorigenesis.