Ketohexokinase is involved in fructose utilization and promotes tumor progression in glioma

Highlights: • KHK was overexpressed in glioma and correlated with glioma malignancy and patients' poor survival. • Silencing KHK could significantly inhibit glioma cell proliferation and migration in fructose medium. • Culturing glioma cells in fructose medium could promote the expression of KHK and increase cells malignancy progression. Many studies have pinpointed that fructose could be utilized as a carbon source in some cancers, and we also defined that glioma cells could utilize fructose to maintain themselves survival and proliferation depending on GLUT5 expression recently. However, ketohexokinase (KHK), as a key enzyme involved in fructose catabolism, drew less attention in cancers, especially in glioma. In the present study, we first analyzed the expression levels of KHK in glioma tissues and the correlations of KHK expression with clinicopathological variables of patients with glioma. Meanwhile, we detected the effect of silencing KHK on the biological functions of glioma cells in fructose medium. From the results, we found that KHK was expressed at significantly higher level in glioma tissues than in non-tumor brain, and KHK expression was significantly correlated with tumor malignancy and poor survival of glioma patients (p < 0.01). Functionally, knockdown of KHK could significantly inhibit cell proliferation and migration of glioma cells in fructose medium. Furthermore, we investigated the KHK expression level after long-time treatment with fructose, and detected the change of cell biological behaviour, then we found that the expression level of KHK was significantly increased and these cells showed more malignant properties. Taken together, our results suggest that high fructose diet and KHK overexpression are correlated with glioma malignant progression and patients' poor survival, and we believe this hypothesis would open the door for novel therapeutic agents and mentalities for glioma.