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

Laure Perrin-Cocon, Pierre Olivier Vidalain, Clémence Jacquemin, Anne Aublin-Gex, Keedrian Olmstead, Baptiste Panthu, Gilles Jeans Philippe Rautureau, Patrice André, Piotr Nyczka, Marc Thorsten Hütt, Nivea Amoedo, Rodrigue Rossignol, Fabian Volker Filipp, Vincent Lotteau, Olivier Diaz

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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.

Original languageEnglish
Article number217
JournalCommunications Biology
Volume4
Issue number1
DOIs
StatePublished - Dec 2021

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