Histone H3K18 lactylation fuels MTHFD2-driven SAM biosynthesis to promote SPINT2 promoter hypermethylation and ovarian cancer progression

Lactate-dependent histone modification represents a novel histone mark that links glycolytic metabolites with the epigenetic process of lactylation. Metabolic reprogramming and epigenetic alterations are pivotal in cancer progression. However, the specific role of histone lactylation in ovarian cancer (OC) remains unclear. Histone lactylation in OC was measured by immunoblotting and immunohistochemistry. Lactylation was inhibited using glycolysis inhibitors and LDHA knockdown. H3K18la target genes were identified by CUT&Tag and RNA-seq, with MTHFD2 validated at the chromatin binding, transcriptional, and protein expression level. Then, potential downstream genes were selected from genome-wide DNA methylation changes by whole-genome sequencing following MTHFD2 knockdown. OC specimens showed significantly higher H3K18 lactylation than the normal ovary. Glycolysis inhibition and LDHA gene knockdown effectively corrected the aberrant lactylation, thereby impeding OC progression both in vivo and in vitro. H3K18la enrichment at the MTHFD2 promoter activated its transcription, contributing to OC pathogenesis. Increased MTHFD2 expression enhanced SPINT2 promoter methylation, silencing its expression and promoting OC development. H3K18la reprograms MTHFD2 activity, increasing S-adenosylmethionine biosynthesis, and this process enhances the DNA methylation-dependent transcriptional silencing of SPINT2 , promoting OC progression. The results revealed a significant link between lactate metabolism reprogramming and epigenetic regulation, suggesting a new lactylation-based therapeutic strategy for OC patients.