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

ABSTRACT: HK2 is expressed in the hepatocellular carcinoma cell line Huh7 while GCK is expressed in the normal hepatocyte. In order to analyze the functional consequences of the expression of one or other of the hexokinases (HK2 or GCK) we have invalidated the expression of HK2 and induced the expression of GCK in Huh7 cells. We analyzed transcriptome of both cell line

ORGANISM(S): Homo sapiens

PROVIDER: GSE144214 | GEO | 2021/01/15

REPOSITORIES: GEO

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

Project description: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.

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CRISPR/Cas9 screens reveal that hexokinase 2 enhances cancer stemness and tumorigenicity

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Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis

Project description:Hexokinases (HK) catalyze the first step of glycolysis and thereby limit its pace. HK2 is highly expressed in the gut epithelium, plays a role in immune responses and is upregulated in inflammation and ulcerative colitis 1-3. Here, we examined the microbial regulation of HK2 and its impact on intestinal inflammation by generating mice lacking HK2 specifically in intestinal epithelial cells (Hk2∆IEC). Hk2∆IEC mice were less susceptible to acute intestinal inflammation upon challenge with dextran sodium sulfate (DSS). Analyzing the epithelial transcriptome from Hk2∆IEC mice during acute colitis revealed downregulation of cell death signaling and mitochondrial dysfunction dependent on loss of HK2. Using intestinal organoids derived from Hk2∆IEC mice and Caco-2 cells lacking HK2, we identified peptidyl-prolyl cis-trans isomerase (PPIF) as a key target of HK2-mediated regulation of mitochondrial permeability and repression of cell-death during intestinal inflammation. The microbiota strongly regulated HK2 expression and activity. The microbially-derived short-chain fatty acid (SCFA) butyrate repressed HK2 expression and oral supplementation protected wildtype but not Hk2∆IEC mice from DSS colitis. Our findings define a novel mechanism how butyrate may act as a protective factor for intestinal barrier homeostasis and suggest targeted HK2 inhibition as a promising therapeutic avenue in intestinal inflammation.

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microRNA-143 downregulates Hexokinase 2 in colon cancer cells

Project description:MicroRNAs (miRNAs) have emerged as important gene regulators and are recognized as key players in tumorigenesis. miR-143 is reported to be down-regulated in several cancers, but knowledge of its targets in colon cancer remains limited. To investigate the role of miR-143 in colon cancer, we have employed a microarray based approach to identify miR-143 targets. Based on seed site enrichment analyses and unbiased word analyses, we found a significant enrichment of miRNA binding sites in the 3M-bM-^@M-^Y-untranslated regions (UTRs) of transcripts down-regulated upon miRNA overexpression. Here we identify Hexokinase 2 (HK2) as a direct target of miR-143 and show that re-introduction of miR-143 in the colon cancer cell line DLD-1 results in a decreased lactate secretion, indicating that miR-143 down-regulation of HK2 affects glucose metabolism in colon cancer cells. DLD-1 cells were transfected with 50 nM miR-143 duplex or mock transfected. Total RNA was harvested 24 hours post-transfection and analyzed on Affymetrix HG-U133 Plus 2.0 human arrays.

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microRNA-143 downregulates Hexokinase 2 in colon cancer cells

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Hexokinase 2 is a transcriptional targetHexokinase 2 is a transcriptional target and a positive modulator of AHR signalling and a positive modulator of AHR signalling

Project description:The Aryl Hydrocarbon Receptor (AHR) regulates the expression of numerous genes in response to activation by agonists including xenobiotics. Although it is well appreciated that environmental signals and cell intrinsic features may modulate this transcriptional response, how it is mechanistically achieved remains poorly understood. We show that Hexokinase 2 (HK2) a metabolic enzyme fuelling cancer cell growth, is a transcriptional target of AHR as well as a modulator of its activity. Expression of HK2 is positively regulated by AHR upon exposure to agonists both in human cells and in mice lung tissues. Conversely, over-expression of HK2 regulates the abundance of many proteins involved in the regulation of AHR signalling and these changes are linked with altered AHR expression levels and transcriptional activity. HK2 expression also shows a negative correlation with AHR promoter methylation in tumours, and these tumours with high HK2 expression and low AHR methylation are associated with a worse overall survival in patients. In sum, our study provides novel insights into how AHR signalling is regulated which may help our understanding of the context-specific effects of this pathway and may have implications in cancer.

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