A positive feedback loop of HK3-mediated activation of NF-κB modulates glucose metabolism and promotes proliferation and metastasis in glioblastoma.

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid proliferation and strong invasive potential. Individuals with GBM usually have a short survival period. However, the metabolic mechanisms driving GBM progression remain incompletely understood. This study aimed to elucidate the role of hexokinase-3 (HK3) in regulating glucose metabolism, proliferation, and invasion of GBM cells. Through integrative analysis of metabolism-related genes in TCGA and GEO datasets, we identified 20 commonly upregulated genes and 47 commonly downregulated genes. Among the above 67 dysregulated genes, high expression of TCIRG1, SLC25A43, SCNN1B, HK3 and HEXB was obviously correlated prognosis in GBM. Then, our attention focused on HK3 which was highly expressed in GBM and associated with advanced clinical stage and poor prognosis. In addition, we found that decreased HK3 expression evidently reduced the glucose uptake and lactate secretion. Functionally, we confirmed that knockdown of HK3 distinctly suppressed the proliferation, migration and invasion of GBM cells via regulating NF-κB signaling pathway. Importantly, the NF-κB signaling molecular RelA (p65) was observed to directly target HK3 promoter. Furthermore, we presented evidences that HK3 and NF-κB signaling could form a feedback loop in regulating GBM cellular glucose metabolism. Overall, our study reveals a novel HK3-driven signaling loop that modulates the proliferation, metastasis and glucose metabolism in GBM, providing potential prognostic and therapeutic targets for GBM.