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

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.

Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters

“…Furthermore, during the process of hepatocarcinogenesis hexokinase expression can switch from isozyme HK4 to HK2, making hepatocellular carcinoma (HCC) cells insensitive to the anti-neoplastic activity of Natural Killer (NK) cells [ 45 ], even if the mechanisms underlying this regulation of innate immunity remain to be elucidated.…”

“…HCC treatment with thyroid hormone T3 in a rat model of hepatocarcinogenesis switches back to HK4 expression and is associated with a metabolic reprogramming towards an oxidative phosphorylation (OXPHOS) phenotype, abrogating HCC progression [ 53 ]. In addition, HK2 is connected to poor prognosis ( Table 1 ) in colorectal cancer [ 54 ], glioblastoma multiforme [ 55 ], pancreatic cancer [ 56 ], cervical squamous cell carcinoma [ 39 , 57 ], prostate cancer [ 58 ], head and neck squamous cell carcinoma [ 59 ], HCC [ 45 ] and other tumor types [ 3 ], and two independent meta-analyses in tumors of the digestive system indicate HK2 as a negative prognostic marker associated with shorter overall survival and progression free survival [ 60 , 61 ]. (Over)expression of HK2 is also linked to tumor progression and/or metastasis in a variety of diverse neoplastic models ( Table 1 ) including HCC [ 62 ], colorectal carcinoma [ 54 ], lung cancer, breast cancer [ 15 ], prostate cancer [ 58 , 63 , 64 ], diffuse large B-cell lymphoma [ 65 ] and glioblastoma [ 66 ].…”

Deoxyribonuclease 1-like 3 Inhibits Hepatocellular Carcinoma Progression by Inducing Apoptosis and Reprogramming Glucose Metabolism

“…Hexokinase (HK) family catalyzes the first critical step in glycolysis, in which glucose is phosphorylated to glucose 6 phosphate (G-6-P). HK2 serves as one of the HK family members has the highest affinity for glucose and is up-regulated in liver cancer, which is associated with poor prognosis [5]. Besides, 6-phosphofructokinase1 (PFK1) served as a rate-limiting enzyme catalyzes the second phosphorylation of glycolysis pathway.…”

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

“…Furthermore, hepatic tissue-resident NK cells also appear to be highly sensitive to lactic acid, which prompts mitochondrial dysfunction, and ultimately, apoptosis [83,84]. HCC glycolysis therefore interferes with the function of the innate immune system in the TME, ablating interferon signaling and NK cell cytotoxicity [85].…”