ArticleCell death & disease2020
Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 68 citations in OpenAlex.
- Bibliometric Analysis of ATAC-Seq and Its Use in Cancer Biology via Nucleic Acid Detection.Frontiers in medicine · 2020Pooled it
- The "Selfish Cell": The Central Role of Metabolism in Relaying Environmental Stimuli and Controlling Cellular Function.Biology · 2026Review
- Alterations to the yeast chromatin landscape during hypoxia.bioRxiv : the preprint server for biology · 2026Article
- A Modular Liver-Microbial Microfluidic Platform to Evaluate Therapeutic and Adverse Effects of Microbial Metabolites.Advanced healthcare materials · 2026Article
- Amino Acids as Targets for Immunotherapy against Solid Tumors.Cell biochemistry and biophysics · 2026Review
- Hypoxic regulation of chromatin and gene transcription.Communications biology · 2026Article
- Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis.Nature communications · 2026Article
- Short-chain fatty acids in the tumor microenvironment: from molecular mechanisms to cancer therapy.Theranostics · 2026Review
- Epigenetic crosstalk in neuroblastoma development and progression.Frontiers in cell and developmental biology · 2026Review
- Transcriptional condensates enrich phosphorylated PRMT2 to stimulate H3R8me2a deposition and hypoxic response in glioblastoma.Science China. Life sciences · 2026Article
- Advances in ferroptosis research in ovarian cancer: molecular mechanisms and therapeutic perspectives.American journal of cancer research · 2026Review
- Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Targeting pyruvate metabolism generates distinct CD8+ T cell responses to gammaherpesvirus and B lymphoma.JCI insight · 2025Article
- Extracellular Vesicles in cancer: from isolation and characterization to metastasis, drug resistance, and clinical applications.BMC cancer · 2025Review
- Rotenone adaptation promotes migration and invasion of p53-wild-type colon cancer through lipid metabolism.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Article
- AC129507.1 is a ferroptosis-related target identified by a novel mitochondria-related lncRNA signature that is involved in the tumor immune microenvironment in gastric cancer.Journal of translational medicine · 2025Article
- FGF2 supports NANOG expression via pyruvate dehydrogenase-dependent histone acetylation under low oxygen conditions.Frontiers in cell and developmental biology · 2025Article
- Green Radish Polysaccharides Ameliorate Hyperlipidemia in High-Fat-Diet-Induced Mice via Short-Chain Fatty Acids Production and Gut Microbiota Regulation.Foods (Basel, Switzerland) · 2024Article
- Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis.Cell death & disease · 2024Article
- Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production.Molecular metabolism · 2024Article
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
Despite the fact that Otto H. Warburg discovered the Warburg effect almost one hundred years ago, why cancer cells waste most of the glucose carbon as lactate remains an enigma. Warburg proposed a connection between the Warburg effect and cell dedifferentiation. Hypoxia is a common tumor microenvironmental stress that induces the Warburg effect and blocks tumor cell differentiation. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma differentiation model, we discovered that hypoxia repressed cell differentiation through reducing cellular acetyl-CoA levels, leading to reduction of global histone acetylation and chromatin accessibility. The metabolic switch triggering this global histone hypoacetylation was the induction of pyruvate dehydrogenase kinases (PDK1 and PDK3). Inhibition of PDKs using dichloroacetate (DCA) restored acetyl-CoA generation and histone acetylation under hypoxia. Knocking down PDK1 induced neuroblastoma cell differentiation, highlighting the critical role of PDK1 in cell fate control. Importantly, acetate or glycerol triacetate (GTA) supplementation restored differentiation markers expression and neuron differentiation under hypoxia. Moreover, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduced chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. In addition, hypoxia-induced histone hypermethylation by increasing 2-hydroxyglutarate (2HG) and reducing α-ketoglutarate (αKG). αKG supplementation reduced histone hypermethylation upon hypoxia, but did not restore histone acetylation or differentiation markers expression. Together, these findings suggest that diverting pyruvate flux away from acetyl-CoA generation to lactate production is the key mechanism that Warburg effect drives dedifferentiation and tumorigenesis. We propose that combining differentiation therapy with acetate/GTA supplementation might represent an effective therapy against neuroblastoma.
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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.