SIRT4 Promotes Pancreatic Cancer Stemness by Enhancing Histone Lactylation and Epigenetic Reprogramming Stimulated by...

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.