H3K18 lactylation promotes glycolysis in bladder cancer via inhibiting GNG7 through regulating PI3K-AKT signaling pathway.

Bladder cancer (BLCA) is a malignant neoplasm arising from the bladder mucosa, with clinical manifestations including hematuria, dysuria, and urinary frequency. The G Protein Subunit Gamma 7 (GNG7) gene encodes the gamma subunit of heterotrimeric G proteins, which is pivotal in signal transduction cascades. Lactylation, a post-translational modification induced by lactate, has been investigated in various tumor conditions. This study sought to explore the role of histone H3 lysine 18 lactylation (H3K18la) in BLCA and its underlying mechanisms. Cell viability and migration were evaluated using MTT and Transwell migration assays, respectively. The protein levels of lactylation and H3K18la were detected via Western blot. Glucose uptake, lactate production, and extracellular acidification rate were measured using commercial kits. Chromatin immunoprecipitation-qPCR was employed to determine the relative enrichment of H3K18la on the GNG7 promoter. Additionally, a tumor-bearing mouse model was established. The results indicated that GNG7 expression was downregulated in BLCA cells. Furthermore, overexpression of GNG7 inhibited glycolysis in BLCA cells and reduced tumor growth in xenograft mice. BLCA cells also exhibited elevated protein levels of pan-Kla and H3K18la. Mechanistically, H3K18la suppressed the transcriptional activity of GNG7 in BLCA cells. Moreover, deficiency of GNG7 enhanced cell viability, migration, and glycolysis in BLCA cells. It was further found that GNG7 inhibited the activation of the phosphoinositide 3-kinase-protein kinase B (PI3K-AKT) signaling pathway in BLCA. In summary, H3K18la promotes glycolysis in BLCA by inhibiting GNG7 through the regulation of the PI3K-AKT signaling pathway, which may offer a new perspective for BLCA treatment.