Cyclin B2 facilitates glycolysis and tumor progression in pancreatic ductal adenocarcinoma by promoting histone lactylation.

BACKGROUND: Cyclin B2 (CCNB2), a member of the cyclin family, plays a crucial role in glycolysis and the progression of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modifications, particularly histone lactylation, have emerged as novel markers associated with glycolysis. However, the specific mechanisms by which CCNB2 influences histone lactylation in PDAC remain unclear. METHODS: We investigated the involvement of CCNB2 in PDAC growth and progression using glycolysis inhibitors in vivo and in vitro. The expression levels of CCNB2 in PDAC were assessed through bioinformatics analysis, Western blotting, and immunohistochemistry. Additionally, we analyzed the correlation between CCNB2 expression and patient prognosis using online databases. By manipulating CCNB2 expression in PDAC cells, we examined changes in malignant biological phenotypes. Finally, we explored the relationship between CCNB2 and histone lactylation (specifically H3K18la) by investigating its interactions with LDHA/LDHB and TTK/BUB1B. RESULTS: Glycolytic inhibitors significantly suppressed PDAC cell proliferation both in vitro and in vivo, accompanied by reduced CCNB2 expression. Analysis of online databases revealed that CCNB2 expression was markedly elevated in PDAC tissues, and patients with high CCNB2 expression exhibited poorer prognoses. Further experiments confirmed higher CCNB2 expression in PDAC cells compared to normal cells and tissues. Knockdown of CCNB2 significantly inhibited PDAC cell proliferation, invasion, and migration, while reducing the expression of glycolytic-related proteins HK II, GLUT1, and PKM2, potentially via the PI3K/AKT signaling pathway. CCNB2 knockdown also decreased the expression of LDHA and LDHB, downregulated H3K18la levels, reduced TTK and BUB1B expression, and lowered lactic acid production. CONCLUSION: The glycolysis-CCNB2-H3K18la-TTK/BUB1B signaling axis exacerbates the malignant progression of PDAC, providing insights into potential lactylation-based therapeutic strategies for this disease.