A hexokinase isoenzyme switch in human liver cancer cells promotes lipogenesis and enhances innate immunity

• Published in: Communications biology 2021-02, Vol.4 (1), p.217-15, Article 217
• Main Authors: Perrin-Cocon, Laure, Vidalain, Pierre-Olivier, Jacquemin, Clémence, Aublin-Gex, Anne, Olmstead, Keedrian, Panthu, Baptiste, Rautureau, Gilles Jeans Philippe, André, Patrice, Nyczka, Piotr, Hütt, Marc-Thorsten, Amoedo, Nivea, Rossignol, Rodrigue, Filipp, Fabian Volker, Lotteau, Vincent, Diaz, Olivier
• Format: Article
• Language: English
• Subjects: 13/109; 13/21; 13/44; 13/89; 14/34; 14/63; 38/1; 38/39; 38/91; 42; 631/67/2327; 631/67/580; 82/58; 96/10; Affinity; Biochemistry, Molecular Biology; Biology; Biomedical and Life Sciences; Cancer; Carcinogenesis; CRISPR; Genomics; Glucokinase; Glycogen; Glycolysis; Hepatocellular carcinoma; Hepatocytes; Hexokinase; Human health and pathology; Hépatology and Gastroenterology; Immune response; Immunology; Innate immunity; Life Sciences; Lipogenesis; Lipoproteins (very low density); Liver cancer; Medical prognosis; Metabolism; Mitochondria; Natural killer cells; Therapeutic targets; Tumors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-01749-3

During the cancerous transformation of normal hepatocytes into hepatocellular carcinoma (HCC), the enzyme catalyzing the first rate-limiting step of glycolysis, namely the glucokinase (GCK), is replaced by the higher affinity isoenzyme, hexokinase 2 (HK2). Here, we show that in HCC tumors the highest expression level of HK2 is inversely correlated to GCK expression, and is associated to poor prognosis for patient survival. To further explore functional consequences of the GCK-to-HK2 isoenzyme switch occurring during carcinogenesis, HK2 was knocked-out in the HCC cell line Huh7 and replaced by GCK , to generate the Huh7- GCK + / HK2 − cell line. HK2 knockdown and GCK expression rewired central carbon metabolism, stimulated mitochondrial respiration and restored essential metabolic functions of normal hepatocytes such as lipogenesis, VLDL secretion, glycogen storage. It also reactivated innate immune responses and sensitivity to natural killer cells, showing that consequences of the HK switch extend beyond metabolic reprogramming. Many cancers fuel their rapid growth by replacing glucokinase with its higher affinity isoenzyme, hexokinase 2 (HK2), making HK2 an attractive drug target. In this study, Perrin-Cocon and Vidalain et al. use CRISPR/Cas-9 gene editing to reverse this enzymatic switch in human liver cancer cells, and find this restores innate immune function as well as reversing cancer-associated metabolic reprogramming.