Effect of overepression of HK1 in hepatocellular carcinoma cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE297965 | GEO | 2026/03/18
REPOSITORIES: GEO
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Project description:Purpose: The goals of this study are to compare the gene expression profile of Huh7 cells treated with different ectosomes or not and to evaluate the function of ectosomal Hexokianse 1 (HK1) derived from HSCs. Methods: Firstly, we treated different LX-2 HSCs with TGF-β (2 ng/mL) for 36 hours to activate HSCs, then ectosomes from LX-2 or HK1-KD LX-2 culture medium were isolated respectively by differential centrifugation processes. Secendly, Huh7 cells were preincubated with different ectosomes or not for 12 hours and then fresh medium for another 12 hours. Lastly, different groups of Huh7 cells were prepared for RNA-seq. Results: By Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the differentially expressed genes, a total of 124 pathways were found to be enriched in the ectosome-incubated Huh7 cells compared with the control Huh7 cells, while a total of 36 pathways were enriched in the ectosome-incubated Huh7 cells compared with the HK1-KD ectosome-incubated Huh7 cells.Gene set enrichment analysis (GSEA) also revealed enrichment of the N-glycosylation pathway in the ectosome-incubated Huh7 cells compared with the control Huh7 cells. Conversely, this pathway was negatively regulated in Huh7 cells incubated with HK1-KD HSC-derived ectosomes Conclusion: the transferal of HSC-derived ectosomal HK1 into HCC cells regulates the N-glycosylation level of Huh7.
2024-04-28 | GSE173632 | GEO
Project description:A primary role of the liver is to regulate whole body glucose homeostasis. Glucokinase (GCK) is the main hexokinase (HK) expressed in hepatocytes and functions to phosphorylate the glucose that enters via GLUT transporters to become glucose-6-phosphate (G6P), which subsequently commits glucose to enter downstream anabolic and catabolic pathways. In the recent years, Hexokinase Domain-Containing-1 (HKDC1), a novel 5th HK, has been characterized by our group and others. Its expression profile varies but has been identified to have low basal expression in normal liver but increases during states of stress including pregnancy, nonalcoholic fatty liver disease (NAFLD), and liver cancer. Here, we have developed a stable overexpression model of hepatic HKDC1 in mice to examine its effect on metabolic regulation. We found that HKDC1 overexpression, over time, causes impaired glucose homeostasis in male mice and shifts glucose metabolism towards anabolic pathways with an increase in nucleotide synthesis. Furthermore, we observed these mice to have larger liver sizes due to greater hepatocyte proliferative potential and cell size, which in part, is mediated via Yes-associated protein (YAP) signaling
2023-03-20 | GSE227535 | GEO
Project description:During the perinatal period, unique metabolic adaptations support energetic requirements for rapid growth. To gain insight into perinatal adaptations, quantitative proteomics were performed comparing the livers of yorkshire pigs at postnatal day seven and adult. These data revealed differences in the metabolic control of liver function including significant changes in lipid and carbohydrate metabolic pathways. Newborn livers showed an enrichment of proteins in lipid catabolism and gluconeogenesis concomitant with elevated liver carnitine and acylcarnitines levels. Sugar kinases were some of the most dramatically differentially enriched proteins comparing neonatal and adult pigs including galactokinase 1 (Galk1), ketohexokinase (KHK), hexokinase 1 (HK1) and hexokinase 4 (GCK). Interestingly, hexokinase domain containing 1 (HKDC1), an enigmatic fifth hexokinase associated with glucose disturbances in pregnant women was highly enriched in the liver during the prenatal and perinatal periods and continuously declined throughout postnatal development in pigs and mice. These changes were confirmed via Western blot and mRNA expression. These data provide new insights into the developmental and metabolic adaptations in the liver during the transition from the perinatal period to adulthood in multiple mammalian species.
2023-07-17 | PXD037264 | Pride
Project description:Among the ways by which oncogenic KRAS upregulates glycolysis in cancer is direct interaction of KRAS4A with Hexokinase 1 (HK1), but the mechanism is unknown. HK1 associates with the outer mitochondrial membrane (OMM) where its allosteric regulation depends on homodimerization. Using affinity capture, FRET and blue native gels we show that KRAS4A enhances oligomerization of HK1 on the OMM. Modeling the HK1/KRAS4A complex with AlphaFold 3 predicts that the membrane association sequences of both HK1 and KRAS4A are oriented toward the OMM. Super-resolution microscopy showed colocalization of HK1 and KRAS4A on the OMM with HK1 enriched at discrete locations. Single-molecule tracking reveals HK1 diffusing freely along the OMM and dwelling at discrete regions where two molecules can be seen to colocalize transiently. KRAS4A expression decreased the diffusion coefficient of HK1 on the organelle. Thus, KRAS4A alters the dynamics of HK1 on the OMM and enhances its activity by promoting oligomerization. The raw mass spectrometric files that confirm the association of KRAS4A with HK1 complexes on the outer mitochondrial membrane are presented here.
2026-02-19 | MSV000100905 | MassIVE
Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).
2023-05-05 | GSE229153 | GEO
Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).
2023-05-05 | GSE229151 | GEO
Project description:FIH catalyzes the asparaginyl hydroxylation of IKKε at asparagine 254,700 and 701
2023-11-23 | PXD047193 |
Project description:Asparagine-linked glycosylation (N-glycosylation), a fundamental modification of proteins synthesized in the endoplasmic reticulum, is easily suppressed by glucose deprivation, but the role of this metabolic link has long remained unclear. We previously identified the activity of mannose metabolism, which branches from glycolysis, as a key determinant for N-glycosylation efficiency in glucose deprivation. Our genetic approach to uncouple mannose metabolism from glycolysis allowed the precise control of mannose metabolic activity via its salvage pathway, revealing that moderate decrease in N-glycosylation efficiency activated the pro-survival PERK-eIF2 signals, which enabled cells to safely cut metabolic costs in N-glycosylation to the minimal levels required for cell survival. In contrast, severe decrease in N-glycosylation efficiency sensitized lysosomes to external insults, thereby biasing cell fates to cell death. Moreover, we demonstrated the specific role of glucose metabolism in regulating global translation efficiency via LKB1. Our study reveals the unexpected role of N-glycosylation as a glucose-sensing mechanism.
2026-03-02 | PXD066382 | Pride
Project description:PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires novel predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER+ breast cancer. Since the transcription factor drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II), changes in FOXM1 expression can be detected using magnetic resonance imaging of LDH-catalyzed hyperpolarized 13C label exchange between pyruvate and lactate but not by PET measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[18F]fluorodeoxyglucose.
| EGAS00001004452 | EGA
Project description:Excess lactate is produced in tumor cells by aerobic glycolysis and regulates gene expressions by histone lactylation. However, how histone lactylation functions under glucose-limited conditions remains unknown. Here, we show that lysine lactylation redistributes to transcription start sites (TSSs) during glucose deprivation, thereby altering biological behaviors in canine hemangiosarcoma (HSA) cells. Glucose deprivation significantly decreased global histone lactylation levels, while lactylation peaks were enriched at TSSs of ATF4‑regulated stress‑response, asparagine-synthesis and immune‑related genes. Stress-response gene expressions were upregulated, and ATF4 polyclonal knockout abrogated this activation. [U-13C]glutamine tracing demonstrated that HSA cells synthesized asparagine from glutamine when glucose was scarce, and asparagine supplementation modestly activated cell proliferation. In HSA patient tissues, H3K18la levels were heterogeneous, and M2-like macrophages preferentially infiltrated tumor regions showing low histone lactylation levels. These findings demonstrate that lysine lactylation regulates transcription that supports tumor cell survival and fosters a pro-tumor microenvironment even under glucose-limited conditions.
2026-01-08 | GSE305701 | GEO