Unraveling the Molecular Network of Glucose Metabolism in Non-Small Cell Lung Cancer: The Role of the EZH2/FBXL7/PFKFB4 Pathway

Non-Small Cell Lung Cancer (NSCLC) is the deadliest cancer worldwide. In this article, Zhou et al. examined the correlation between hypoxia, a common feature of solid tumors, and the malignant phenotype of NSCLC. The authors studied the upstream and downstream mechanisms mediated by F-BoX/LRR-repeat protein (FBXL7), a newly identified E3 ubiquitin ligase that is downregulated in NSCLC. They discovered that FBXL7 downregulation is linked to 6-PhosphoFructo-2-Kinase/Fructose-2,6- Biphosphatase 4 (PFKFB4) protein accumulation that, in turn, contributes to the promotion of glucose metabolism and Warburg effect. In addition, they demonstrated that Enhancer of Zeste Homolog 2 (EZH2), a histone methyltransferase, is responsible for the repression of FBXL7 transcription and is upregulated by the Hypoxia-Inducible Factor 1α (HIF-1α). EZH2 knockdown and FBXL7 overexpression were correlated with reduced glycolysis, cell migration and invasion, and enhanced apoptosis. The study delves into the mechanisms underlying drug resistance and metastasis formation, opening new perspectives on potential therapeutic implications of discovery. One or more of the axis elements may be potential biomarkers and/or drug targets. However, it will be necessary to identify the signaling and metabolic pathways interconnected with the EZH2/FBXL7/PFKFB4 axis and investigate its role in other cancer subtypes.