Histone H3K18 lactylation promotes malignancy progression in non-small cell lung cancer through TCN1 upregulation.

Lung cancer remains the leading cause of cancer-related mortality worldwide, non-small cell lung cancer (NSCLC) is a major histological subtype. Lactylation, a newly discovered post-translational modification, and its impact on lung cancer are still poorly understood. In this study, using immunohistochemical staining and immunofluorescence staining analyses, we found elevated levels of pan-lactyl proteins and histone H3 lysine 18 lactylation (H3K18la) in tumor tissues. Subsequently, siLDHA and siLDHB treatment or Nala treatment were respectively adopted as H3K18la deletion or acquisition functional models to demonstrate the effects of H3K18la on the proliferation, migration and apoptosis phenotypes of NSCLC cells. Through chromatin immunoprecipitation sequencing (ChIP-seq) analysis and ChIP-qPCR experiments, we demonstrate for the first time that lactylation of H3K18 regulates the transcriptional activity of the Transcobalamin 1 (TCN1) promoter. High expression of TCN1 in lung cancer is associated with poor patient prognosis. Functional experiments in vitro and in vivo revealed that knockdown of TCN1 suppressed the malignant progression of NSCLC. Finally, mechanistic investigations uncovered that TCN1 activates the PI3K/AKT signaling pathway. These results reveal a novel mechanism by which H3K18la precisely regulates the promoter activity of specific genes and enhance our understanding of the specific roles of lactate and lactylation in modulating tumor biology. Targeting H3K18la and TCN1 may represent potential therapeutic strategies for NSCLC.