Glycolysis-mediated H3K18la modifications drive aggressive bladder cancer through metabolic and epigenetic...

Metabolic reprogramming and epigenetic alterations contribute to the aggressiveness of human bladder cancer (BC). Lactate-dependent histone modification represents a novel class of histone marks that links the glycolytic metabolite to the epigenetic mechanism of lactylation. However, the role of histone lactylation in BC remains unclear.

The single-cell RNA sequencing dataset GSE135337 was analyzed to assess glycolysis and histone lactylation levels in BC samples. Subsequently, western blotting and immunofluorescence analyses were employed to detect the levels of histone lactylation in BC. The inhibition of histone lactylation, achieved via glycolysis inhibitors or lactate dehydrogenase A (LDHA) knockdown, was confirmed to impede BC growth and progression in both in vitro and in vivo studies. Potential target genes of H3K18 lactylation (H3K18la) were screened through CUT&Tag and RNA-seq analyses.

The study identified a notable increase in glycolytic activity and histone lactylation, especially H3K18la, which correlated with poor prognosis in BC patients. Inhibiting glycolytic activity through various inhibitors or LDHA knockdown led to anti-tumor effects in BC in both in vitro and in vivo studies. CUT&Tag of H3K18la combined with RNA-seq analysis identified four potential target genes (AHNAK2, PVR, SLC7A11, and SREBF1). These genes were found to be associated with the growth and invasion of BC potentially through complex metabolic regulatory mechanisms within the tumor microenvironment.

Glycolysis closely linked to H3K18la enrichment at the AHNAK2, PVR, SLC7A11, and SREBF1 loci, established a correlative epigenetic network that accompanies aggressive BC progression. These findings reveal important connections between lactate metabolism reprogramming and epigenetic regulation, potentially leading to new therapeutic strategies targeting lactylation in BC treatment.