Lipogenesis and innate immunity in hepatocellular carcinoma cells reprogrammed by an isoenzyme switch of hexokinases

Hexokinases catalyse the first step of glycolysis by phosphorylating glucose. In the liver, normal hepatocytes express the low-affinity hexokinase 4, also known as glucokinase (GCK), which is adapting hepatocyte function to glycaemia. Conversely, hepatocellular carcinoma (HCC) cells express the high-affinity hexokinase 2 (HK2) to sustain tumour proliferation even at low glucose concentrations. The analysis of transcriptomic data from human HCC tumours shows that GCK and HK2 expression levels are inversely correlated and associated with patient survival. To explore functional consequences of such a GCK-to-HK2 isoenzyme switch, HK2 was knocked-out in the HCC cell line Huh7 and replaced by GCK. Transcriptomic, metabolomic and immunological profiling revealed that beyond glycolysis, the hexokinase isoenzyme switch rewires central carbon metabolism, promotes lipogenesis, enhances immune functions and restores sensitivity to NK cells. Altogether, our results suggest that the GCK-to-HK2 isoenzyme switch is playing a key role in HCC dedifferentiation and immune escape.