High glucose-induced mitochondrial fission drives pancreatic cancer progression through the H3K18la/TTK/BUB1B signal pathway.

[PURPOSE] Diabetes mellitus is a critical risk factor for pancreatic cancer, yet its underlying molecular mechanism remains unclear. This study aims to investigate whether high glucose levels promote pancreatic cancer progression, and its molecular mechanism.

[METHODS] Tumor samples were collected from pancreatic cancer patients with diabetes mellitus (DM + PC). Additionally, pancreatic cancer animal models were constructed with diabetes/high glucose feeding and high glucose cell culture medium. The expression of p-AMPK, p-DRP1(Ser616), and mitochondrial fission were evaluated through molecular analysis. The levels of lactic acid, H3K18la, TTK, and BUB1B were also evaluated.

[RESULT] Survival analysis indicated that the clinical DM + PC group exhibited significantly worse overall survival (p < 0.05) and expressed significantly elevated levels of p-DRP1(Ser616) and HSP60 (p < 0.05). In the pancreatic cancer animal model with diabetes mellitus, higher tumor volumes and weights were observed along with elevated levels of p-DRP1(Ser616) and HSP60 (p < 0.05). Additionally, the high-glucose medium promoted proliferation and migration in cell lines (p < 0.05) and led to an increased expression of H3K18la, TTK, and BUB1B in a dose-dependent manner (p < 0.05). High levels of H3K18la, L-lactyl lysine, and TTK/BUB1B were expressed in DM + PC group(p < 0.05).

[CONCLUSION] High glucose increases the expression of p-DRP (Ser616) by inhibiting p-AMPK and subsequently affecting mitochondrial fission and lactic acid levels. This process is likely prompted by lactation levels of histone H3 and the expression of BUB1B and TTK.