CDH2-mediated GSK3β/β-catenin dysregulation defines a targetable vulnerability in chronic myeloid leukemia

Background: Chronic myeloid leukemia (CML) is driven by uncontrolled myeloid proliferation, yet underlying molecular mechanisms remain incompletely understood. This study investigated the pan-cancer expression profile of N-cadherin (CDH2) and its specific role in suppressing CML progression via the GSK3β/β-catenin axis. Methods: We combined in silico analyses (TCGA/GEO datasets) with functional assays in K562 cells, assessing CDH2 expression across 31 malignancies and its mechanistic effects on proliferation, cell cycle, apoptosis, and β-catenin/GSK3β signaling. Results: CDH2 was significantly upregulated in 18 malignancies and downregulated in 10. It served as an adverse prognostic factor for overall survival in five solid tumors but a favorable factor in KIRC. In AML, elevated CDH2 correlated with poor-prognosis cytogenetic risk (P=0.008). CDH2 also correlated with macrophage/NK cell recruitment in solid tumors. In K562 cells, CDH2 overexpression suppressed proliferation by inducing cell cycle arrest and early apoptosis. Mechanistically, this occurred through β-catenin sequestration and reduced GSK3β inactivation, lowering free β-catenin levels. Notably, only GSK3 inhibition reversed this anti-proliferative effect. Conclusions: CDH2 exhibits context-dependent roles across malignancies—functioning as a tumor suppressor in CML via non-canonical β-catenin/GSK3β dysregulation, while serving as an adverse prognostic marker in certain solid tumors. This creates a targetable vulnerability to GSK3 inhibitors in myeloid leukemia.