RT Journal Article
SR Electronic
T1 Lipogenesis and innate immunity in hepatocellular carcinoma cells reprogrammed by an isoenzyme switch of hexokinases
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.13.973321
DO 10.1101/2020.03.13.973321
A1 Laure Perrin-Cocon
A1 Pierre-Olivier Vidalain
A1 Clémence Jacquemin
A1 Anne Aublin-Gex
A1 Keedrian Olmstead
A1 Baptiste Panthu
A1 Gilles J. P. Rautureau
A1 Patrice André
A1 Piotr Nyczka
A1 Marc-Thorsten Hütt
A1 Nivea Amoedo
A1 Rodrigue Rossignol
A1 Fabian Volker Filipp
A1 Vincent Lotteau
A1 Olivier Diaz
YR 2020
UL http://biorxiv.org/content/early/2020/11/02/2020.03.13.973321.abstract
AB 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). The transcriptomic analysis of HCC tumors shows that highest expression level of HK2 in tumor lesions 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.Competing Interest StatementThe authors have declared no competing interest.