LDHA-Mediated H3K18 Lactylation Promotes the Glycolysis in Non-Small Cell Lung Cancer Through Targeting PTEN

Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases. Lactylation, a lactate-driven post-translational modification, has been implicated in various tumor pathologies. This study aimed to investigate the role of histone H3 lysine 18 lactylation (H3K18la) in NSCLC progression. Western blot was performed to detect the protein levels of lactylation and H3K18la. Cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and Transwell migration assays were performed to detect the cell viability, proliferation, and migration. The 2-deoxy-2-[fluorine-18]fluoro-D-glucose (¹⁸F-FDG) uptake rate, lactate content, and extracellular acidification rate (ECAR) were detected by commercial kits. Chromatin immunoprecipitation-qPCR was performed to assess the relative H3K18la enrichment on phosphatase and tensin homolog (PTEN) promoter. Finally, we established the tumor-bearing mouse model. Results showed that A549 and H1299 cells showed increased pan-kla and H3K18la protein levels. Besides, silencing of lactate dehydrogenase A (LDHA) inhibited the cell viability, proliferation, migration, and glycolysis in A549 and H1299 cells. Animal study results indicated that LDHA inhibition suppressed the tumor growth in xenografts mice. Mechanically, LDHA-mediated H3K18la regulated the transcription and stability of PTEN in A549 and H1229 cells. Final rescue results demonstrated that PTEN deficiency increased the cell proliferation, migration, and glycolysis in A549 and H1299 cells. Our study suggested that LDHA-mediated H3K18la promoted the glycolysis in NSCLC through targeting PTEN, which might provide a new insight for NSCLC treatment.