A Feedback Circuit Comprising Ehd1 And 14-3-3 Zeta Sustains Beta-Catenin/ C-Myc-Mediated Aerobic Glycolysis And Proliferation In Non-Small Cell Lung Cancer

Mammalian Eps15 homology domain 1 (EHD1) participates in the development of non-small cell lung cancer (NSCLC). However, its role in mediating aerobic glycolysis remains unclear. Herein, microarray analysis revealed that EHD1 expression was significantly correlated with the glycolysis/gluconeogenesis pathway. Clinically, EHD1 expression was positively correlated with the maximum standard uptake value (SUVmax) in 18F-FDG PET/ CT scans. Additionally, EHD1 knockdown inhibited aerobic glycolysis and proliferation in vitro and in vivo. Furthermore, Wnt/beta-catenin signaling was identified as a critical EHD1-regulated pathway. Co-IP, native gel electrophoresis, and immunoblotting showed that EHD1 contributed to 14-3-3 dimerization via 14-3-3 zeta and subsequent activation of beta-catenin/c-Myc signaling. Analysis of the EHD1 regulatory region via ENCODE revealed the potential for c-Myc recruitment, leading to transcriptional activation of EHD1 and formation of an EHD1/14-3-3 zeta/beta-catenin/c-Myc positive feedback circuit. Notably, blocking this circuit with a Wnt/beta-catenin inhibitor dramatically inhibited tumor growth in vivo. The positive correlations among EHD1, 14-3-3 zeta, c-Myc, and LDHA were further confirmed in NSCLC tissues. Collectively, our study demonstrated that EHD1 activates a 14-3-3 zeta/beta-catenin/c-Myc regulatory circuit that synergistically promotes aerobic glycolysis and may constitute a promising therapeutic target for NSCLC.