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

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.