FBXW7 mutations reprogram glucose metabolism by activating the ETV6-GLUT1 axis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Endometrial cancer (EC) progression is linked to metabolic reprogramming.
• Mutations in tumor suppressors and oncogenes, like FBXW7, drive these metabolic changes.

Purpose of the Study:

• To investigate the role of FBXW7 mutations in rewiring glucose metabolism in EC.
• To identify the molecular mechanisms by which FBXW7 loss-of-function impacts EC cell metabolism and proliferation.

Main Methods:

• Investigated the SCF^FBXW7 E3 ubiquitin ligase complex function in EC cells with FBXW7 mutations.
• Assessed the impact of FBXW7 mutations on ETV6 stability and its downstream effects on GLUT1 expression and glucose uptake.
• Utilized pharmacological inhibition of GLUT1 to evaluate its therapeutic potential.

Main Results:

• Loss-of-function FBXW7 mutations lead to ETV6 stabilization by inhibiting its degradation.
• Stabilized ETV6 increases the expression and plasma membrane localization of glucose transporter 1 (GLUT1).
• Enhanced GLUT1 activity fuels aerobic glycolysis and oxidative phosphorylation, accelerating EC cell proliferation.

Conclusions:

• The FBXW7-ETV6-GLUT1 axis is a key driver of metabolic adaptation and progression in FBXW7-mutant EC.
• Targeting GLUT1 presents a promising therapeutic strategy for patients with FBXW7-mutant endometrial cancer.