EPB41 suppresses the Wnt/β-catenin signaling in non-small cell lung cancer by sponging ALDOC

Despite advancements in therapeutic options, the overall prognosis for non-small-cell lung cancer (NSCLC) remains poor. Further exploration of the etiology and targets for novel treatments is crucial for managing NSCLC. In this study, we revealed the significant potential of EPB41 for inhibiting NSCLC proliferation, invasion and metastasis in vitro and in vivo. Consistent with its tumor suppressor role in NSCLC, the expression of EPB41 in NSCLC specimens evidently decreased compared to that in normal tissues, and low EPB41 expression was associated with poor prognoses for NSCLC patients. We further demonstrated the importance of EPB41 protein as a novel inhibitor of the Wnt signaling, which regulates beta-Catenin stability, and elucidated the crucial role of the EPB41/ALDOC/GSK3 beta/beta-Catenin axis in NSCLC. Suppression of EPB41 expression in cancer cells elevated the levels of free ALDOC protein released from the EPB41-ALDOC complex, leading to disassembly of the beta-catenin destruction complex, reduced proteolytic degradation of beta-catenin, elevated cytoplasmic accumulation and nuclear translocation of beta-catenin, thereby activating the expression of multiple oncogenes and, thus, NSCLC pathogenesis. Our study highlights the potential of EPB41 as a future therapeutic target for lung cancer.

Automated summary

Despite the poor overall prognosis of non-small-cell lung cancer (NSCLC), this study highlights the significant potential of EPB41 as a future therapeutic target for inhibiting NSCLC proliferation, invasion, and metastasis. The decreased expression of EPB41 in NSCLC and its role in regulating the Wnt signaling pathway were associated with poor prognoses in NSCLC patients. The study elucidated the crucial role of the EPB41/ALDOC/GSK3 beta/beta-Catenin axis in NSCLC pathogenesis, suggesting EPB41 as a novel inhibitor of the Wnt pathway for potential therapeutic interventions in lung cancer.