SIRT4 Promotes Pancreatic Cancer Stemness by Enhancing Histone Lactylation and Epigenetic Reprogramming Stimulated by Calcium Signaling
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View abstract on PubMed
Summary
This summary is machine-generated.Calcium signaling via α2δ1 upregulates SIRT4, promoting pancreatic cancer stemness. SIRT4 deacetylates ENO1, boosting glycolysis and histone lactylation, which drives epigenetic reprogramming essential for tumor-initiating cells (TICs).
Area Of Science
- Mitochondrial biology
- Cancer epigenetics
- Cell signaling
Background
- Sirtuins, including SIRT4, regulate mitochondrial protein modifications and metabolic reprogramming, influencing cancer progression.
- The upstream regulators and signaling pathways controlling SIRT4's function in cancer remain largely unknown.
Purpose Of The Study
- To elucidate the mechanisms by which calcium signaling influences SIRT4 expression and function in pancreatic cancer.
- To investigate the role of SIRT4 in promoting the stem cell-like properties of pancreatic tumor-initiating cells (TICs).
Main Methods
- Investigated the link between voltage-gated calcium channel subunit α2δ1 and SIRT4 expression in pancreatic TICs.
- Analyzed SIRT4's enzymatic activity, specifically its deacetylation of ENO1 and its impact on RNA-binding and glycolysis.
- Assessed the effects of SIRT4 and modified ENO1 on histone lactylation and downstream epigenetic reprogramming.
Main Results
- α2δ1-mediated calcium signaling upregulates SIRT4 expression in pancreatic TICs.
- SIRT4 deacetylates ENO1 at K358, enhancing its glycolytic activity and lactate production.
- SIRT4-induced ENO1 modification promotes histone lactylation (e.g., H3K9, H3K18), leading to epigenetic reprogramming and activation of stemness pathways.
Conclusions
- The α2δ1-calcium-SIRT4 axis promotes pancreatic cancer stemness through ENO1 deacetylation and histone lactylation-mediated epigenetic reprogramming.
- This pathway highlights a novel mechanism linking mitochondrial function, epigenetics, and cancer stem cell properties.
- Targeting this pathway offers potential therapeutic strategies against pancreatic cancer TICs.
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