The progression of endometrial cancer (EC) involves substantial metabolic reprogramming, frequently driven by mutations in tumor suppressors and oncogenes. In this study, we identify a previously unrecognized pathway through which FBXW7 mutations rewire glucose metabolism in EC cells. Specifically, we demonstrate that loss-of-function mutations in FBXW7 disrupt the SCF FBXW7 E3 ubiquitin ligase complex, resulting in the stabilization of the transcription factor ETV6 by preventing its ubiquitin-mediated degradation. Accumulated ETV6 subsequently enhances the transcriptional activation of glucose transporter 1 (GLUT1), elevating its expression and localization to the plasma membrane. This increased GLUT1 expression significantly enhances glucose uptake, fueling both aerobic glycolysis and oxidative phosphorylation, which collectively accelerate EC cell proliferation and tumor growth. Importantly, targeting GLUT1 pharmacologically partially reverses the proliferative advantage conferred by ETV6 overexpression, highlighting a promising therapeutic vulnerability. Our findings establish the FBXW7-ETV6-GLUT1 regulatory axis as a critical driver of metabolic adaptation and tumor progression, offering potential strategies for targeted therapy in FBXW7 -mutant EC.
Fei et al. (Sat,) studied this question.