ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
SIRT4 Promotes Pancreatic Cancer Stemness by Enhancing Histone Lactylation and Epigenetic Reprogramming Stimulated by Calcium Signaling.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Lactate-induced epithelial-mesenchymal transition: a metabolic nexus in pancreatic cancer metastasis.Translational cancer research · 2026Review
- Unveiling Lactylation: A Novel Frontier in Cancer Stemness and Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Mechanism of Scutellaria baicalensis extracellular vesicles in attenuating Mycoplasma gallisepticum-induced inflammation via TRPC1 - STIM1/ORAI1 channel inhibition.Poultry science · 2026Article
- Enolase 1: A paradigm of metabolic enzyme moonlighting in tumorigenesis (Review).International journal of oncology · 2026Review
- HSP90AB1-Mediated Ubiquitin-Proteasome Degradation of ITGBL1 Promotes Osteosarcoma Progression by Inhibiting Endoplasmic Reticulum Stress-Induced Autophagy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The histone acylation network: emerging therapeutic targets for remodeling the epigenetic landscape in pancreatic ductal adenocarcinoma.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- SIRT4 regulates antiviral and autoimmune responses by promoting cGAS-mediated signaling pathways.EMBO reports · 2026Article
- Lactate-driven lactylation reprograms chondrocyte fate and joint inflammation in osteoarthritis: linking metabolism with epigenetic regulation.Frontiers in cell and developmental biology · 2026Review
- Precise mimicry of physiological CaBioengineering & translational medicine · 2026Article
- Metabolic-epigenetic crosstalk in latent autoimmune diabetes in adults: potential roles of lactate-induced histone lactylation in immune regulation and pancreatic β-cell fate.Frontiers in endocrinology · 2026Review
- Integrative multi-omics profiling identifies a lactylation-associated, metabolically active, and immunosuppressive subtype of colon adenocarcinoma.Molecular & cellular oncology · 2026Article
- From mechanism to targeted therapy: Advances in histone lactylation-driven cancer progression (Review).Oncology letters · 2026Review
- Post-Translational Modifications: Key "Regulators" of Pancreatic Cancer Malignant Phenotype-Advances in Mechanisms and Targeted Therapies.Biomedicines · 2025Review
- Lactylation-driven KRT19 promotes non-small cell lung cancer progression by suppressing cellular senescence.Journal of experimental & clinical cancer research : CR · 2025Article
- Targeting Lactylation for Cancer: Mechanisms, Effects, and Therapeutic Prospects.International journal of molecular sciences · 2025Review
- Lactate and lactylation in cancer: drivers of immune suppression and microenvironmental reprogramming.Experimental hematology & oncology · 2025Review
- SIRT4 Promotes Pancreatic Cancer Stemness by Enhancing Histone Lactylation and Epigenetic Reprogramming Stimulated by Calcium Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Lactate attenuates PANoptosis and enhances ZBP-1 lactylation in macrophages in acute lung injury.Frontiers in immunology · 2025Article
- Stereospecific lactylation in bacteriology: L/D-lactate partitioning shapes host metabolic-disease axis.Frontiers in microbiology · 2025Review
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
Mitochondria Sirtuins including SIRT4 erase a variety of posttranslational modifications from mitochondria proteins, leading to metabolic reprogramming that acts as a tumor suppressor, oncogenic promotor, or both. However, the factors and the underlying mechanisms that stimulate and relay such a signaling cascade are poorly understood. Here, we reveal that the voltage-gated calcium channel subunit α2δ1-mediated calcium signaling can upregulate the expression of SIRT4, which is highly expressed in α2δ1-positive pancreatic tumor-initiating cells (TICs). Furthermore, SIRT4 is functionally sufficient and indispensable to promote TIC properties of pancreatic cancer cells by directly deacetylating ENO1 at K358, leading to attenuated ENO1's RNA-binding capacity, enhanced glycolytic substrate 2-PG affinity, and subsequently robust catalytic activity with boosted glycolytic ability and increased production of lactate acid. Interestingly, both SIRT4 and deacetylated mimetic of ENO1-K358 can increase the lactylation of histones at multiple sites including H3K9 and H3K18 sites, which resulted in epigenetic reprogramming to directly activate a variety of pathways that are essential for stemness. Hence, the study links α2δ1-mediated calcium signaling to SIRT4-mediated histone lactylation epigenetic reprogramming in promoting the stem cell-like properties of pancreatic cancer, which holds significant potential for the development of novel therapeutic strategies by targeting TICs of pancreatic cancer.
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Registered trials
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 Socratic graph.