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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: Not available

| S-EPMC7886870 | biostudies-literature

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

Project description:We identified that HK2 facilitate the maintenance and self-renewal of liver cancer stem cells (CSCs). Moreover, HK2 exerts its function by enhancing the accumulation of acetyl-CoA and epigenetically activating the transcription of acyl-CoA synthetase long chain family member 4 (ACSL4), leading to an increase in fatty acid β-oxidation (FAO) activity.

2022-05-06 | GSE184798 | GEO

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.

2012-05-01 | E-GEOD-33420 | biostudies-arrayexpress

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.

2021-12-01 | GSE158026 | GEO

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

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

| PRJNA603281 | ENA

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 3’-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.

2012-05-02 | GSE33420 | GEO

Hexokinase 2 is dispensable for T cell-dependent immunity

Project description:Hexokinase 2 (HK2) is one the most highly upregulated enzymes in glycolysis in activated T cells and cancer cells. We genetically abolished HK2 expression in T cells in vivo and infected mice with LCMV to induce T cell proliferation. CD8+ T cells from were sorted from spleens of WT and HK2 null mice 8 days after infection. Additionally, WT CD8+ T cells were compared to WT primary T cell acute lymphoblastic leukemia (T-ALL). T-ALL cells were sorted from spleens of mice 6 weeks after adoptive transfer of bone marrow that overexpresses mutant Notch1 (Notch1-deltaE).

2018-08-13 | GSE118326 | GEO

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.

2022-05-31 | PXD028992 | Pride

Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis (CUT&Tag)

Project description:Lactate was implicated in activation of hepatic stellate cells (HSCs). However, the mechanism by which lactate exerts its effect remains elusive. We show that hexokinase 2 (HK2) is sufficient to change gene expression by histone lactylation but not histone acetylation. Using RNA-seq and CUT&Tag chromatin profiling, we found that induction of HK2 expression in activated HSCs is required for the induced gene expression by elevating histone lactylation. Inhibiting histone lactylation by Hk2 deletion or pharmacological inhibition of lactate production diminishes HSC activation, whereas exogenous lactate but not acetate supplementation rescues the activation phenotype. Thus, lactate produced by activated HSCs determines the HSC fate via histone lactylation. We found that histone acetylation competes with histone lactylation, which could explain why class I HDAC inhibitors impede HSC activation. Finally, HSC-specific or systemic deletion of HK2 inhibits HSC activation and liver fibrosis in vivo. Therefore, we provide evidence that HK2 may be an effective therapeutic target for liver fibrosis.

2023-05-05 | GSE229154 | GEO

The mitochondrial metabolic enzyme Hexokinase 2 regulates stem cell function and differentiation by increasing chromatin openness and the accessibility of stem cell genes [ChIP-Seq]

Project description:Mitochondrial metabolites regulate the function and differentiation of leukemic and normal stem cells by affecting epigenetic marks. However, it is less understood how mitochondrial enzymes localize to the nucleus to control stem cell function. We discovered that the mitochondrial metabolic enzyme Hexokinase 2 (HK2) localizes to the nucleus in leukemic and normal hematopoietic stem cells. Overexpression of nuclear HK2 increased leukemic stem cell (LSC) properties and decreased differentiation while selective knockdown of nuclear HK2 promoted differentiation and decreased stem cell function. The nuclear localization of HK2 was phosphorylation dependent and required active import and export. Nuclear HK2 regulated LSC and differentiation independent of its enzymatic and metabolic activity. HK2 interacted with nuclear proteins that regulate chromatin openness and increased chromatin accessibilities at sites associated with the LSC+ signature and DNA damage repair. Consistent with these effects, nuclear HK2 increased repair of DNA damage and contributed to the mechanism by which LSCs resist DNA damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes regulate gene expression and stem cell function independent of their metabolic function.

2022-03-15 | GSE176072 | GEO

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