ArticleThe Journal of clinical investigation2021
Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 113 citations in OpenAlex.
- Thromboxane A2 receptor signalling amplifies osteoclastogenesis in rheumatoid arthritis through ACSL1 associated mitochondrial oxidative metabolism.Nature communications · 2026Article
- Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.Signal transduction and targeted therapy · 2026Review
- Article
- Maternal hyperglycemia-induced O-GlcNAcylation of CaMKIIδ promotes mtDNA release and cardiac remodeling in offspring.Nature communications · 2026Article
- O-GlcNAcylation: the metabolic-immune translator in tumor evolution and treatment.Molecular medicine (Cambridge, Mass.) · 2026Review
- From linear methylation to spatial metabolic control: Rethinking DNMT1 targeting in MASLD: Letter to the editor on "DNMT1 facilitates the progression of MASLD by impeding transcription mediated by HNF4α and PPARα".Clinical and molecular hepatology · 2026Article
- Site-Specific and Quantitative O-GlcNAc Proteomics for Hepatocellular Carcinoma.Journal of proteome research · 2026Article
- Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes.Aging cell · 2026Article
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- Decoding the regulatory code: O-GlcNAcylation in epithelial-mesenchymal transition (EMT).The Journal of biological chemistry · 2026Review
- Article
- GFAT2-mediated HSPD1 O-GlcNAcylation drives chemotherapy resistance in non-small cell lung cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- Regulatory mechanism of O-linked N-acetylglucosamine protein modification on autophagy in cancer.Clinical and translational medicine · 2026Review
- Post-Translational Modifications of Histones and Non-Histones in Liver Disease and Traditional Chinese Medicine Treatment: A Narrative Review.Pharmacogenomics and personalized medicine · 2026Review
- O-GlcNAcylation stabilizes RSK4 by antagonizing GSK3β-mediated phosphorylation to enhance radioresistance in esophageal squamous cell carcinoma.International journal of biological sciences · 2026Article
- Molecular regulatory network of glycolytic reprogramming in hepatocellular carcinoma and its clinical implications.Biological procedures online · 2025Review
- Glutamine: fructose-6-phosphate amidotransferase (GFAT) in the pathology of diseases: a review.Cell death discovery · 2025Review
- FUT3 mediated GRP78 fucosylation promotes colorectal cancer survival and proliferation under glucose restriction via PERK/ATF4/STC2 axis.NPJ precision oncology · 2025Article
- Protective effect of phosphoenolpyruvate carboxykinase 1 on inflammation and fibrotic progression of IgA nephropathy.Renal failure · 2025Article
- Molecular network of metabolic reprogramming and precision diagnosis and treatment of hepatocellular carcinoma.Biomarker research · 2025Review
10 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although cancer cells are frequently faced with a nutrient- and oxygen-poor microenvironment, elevated hexosamine-biosynthesis pathway (HBP) activity and protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor and are emerging hallmarks of cancer. Inhibiting O-GlcNAcylation could be a promising anticancer strategy. The gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) is downregulated in hepatocellular carcinoma (HCC). However, little is known about the potential role of PCK1 in enhanced HBP activity and HCC carcinogenesis under glucose-limited conditions. In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low-glucose conditions. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo uridine triphosphate synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation, promoting UDP-GlcNAc synthesis for elevated O-GlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation, counteracting its stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride and 6-diazo-5-oxo-L-norleucine blocked HBP-mediated O-GlcNAcylation and suppressed tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.