Histone lactylation promoted colorectal cancer progression by enhancing tumor necrosis factor transcription and served as a diagnostic biomarker

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, with unmet needs for early diagnostic biomarkers and therapeutic targets. Recent studies highlight the role of histone lactylation (H3K18la) in modulating gene expression and tumor progression. Its specific mechanisms in CRC, however, remain poorly understood. This study analyzed 60 CRC patients to evaluate H3K18la levels in tumor and adjacent nontumor tissues via Western blot and correlated them with clinical parameters. CRC cell lines were treated with sodium lactate (Nala) to investigate H3K18la's regulatory effects on tumor necrosis factor (TNF) transcription. Mechanistic insights were derived from RNA sequencing, chromatin immunoprecipitation (ChIP) assays, luciferase reporter assays, and RT-qPCR. Diagnostic potential was assessed using receiver operating characteristic curve analysis. H3K18la levels were significantly elevated in CRC tissues compared with adjacent tissues and exhibited high diagnostic accuracy. High H3K18la expression correlated with larger tumor size and advanced american joint committee on cancer (AJCC) stages. Furthermore, H3K18la levels positively correlated with serum carcinoembryonic antigen and carbohydrate antigen 19-9. Nala treatment enhanced H3K18la enrichment at the TNF promoter, upregulating TNF transcription in CRC cells. Mechanistically, H3K18la directly activated TNF promoter activity, as demonstrated by luciferase reporter assays and ChIP analysis. In conclusion, H3K18la serves as a promising diagnostic biomarker for CRC, with strong correlations to tumor progression. Its oncogenic role is mediated, at least partially, through transcriptional activation of TNF. These findings position H3K18la as a novel therapeutic target for CRC and underscore its potential for early detection and personalized treatment strategies.