A hexokinase isoenzyme switch in human liver cancer cells promotes lipogenesis and enhances innate immunity
Open Access
- 16 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Communications Biology
- Vol. 4 (1), 1-15
- https://doi.org/10.1038/s42003-021-01749-3
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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA154887)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (GM115293)
- Fondation pour la Recherche Médicale (DEQ20160334893)
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