A hypoxia/necrosis-driven metabolic-epigenetic axis H3K9 lactylation-mediated SKP2 signaling promotes glioblastoma progression

Abstract Tumor hypoxia/necrosis as a hallmark of glioblastoma (GBM) is strongly associated with malignant progression and poor prognosis of GBM, however, its roles and mechanisms in the behaviors of neighboring surviving GBM cells remain poorly understood. Here, we analyzed public transcriptomic datasets to characterize gene expression in hypoxic/necrotic regions in GBM, and found that the glycolytic pathway was activated in tumor cells from these regions. Furthermore, glycolysis was also elevated in GBM cells under hypoxia/necrosis-mimicking conditions in vitro. Notably, hypoxia/necrosis-mimicking cells-derived lactate promoted the viability and proliferation and migration of neighboring surviving GBM cells. Mechanistically, lactate induced the lactylation of histone H3 lysine 9 (H3K9la), activating transcription of S-phase kinase-associated protein 2 (SKP2). This transcriptional activation was associated with H3K9la enrichment at the SKP2 promoter in GBM cells. SKP2 knockdown inhibited the tumor-promoting effects induced by lactate in GBM cells. Finally, in the orthotopic murine GBM model, hypoxia/necrosis-mimicking cells promoted GBM progression via SKP2 signaling. These results identify a hypoxia/necrosis-driven metabolic-epigenetic axis in GBM, in which lactate-mediated H3K9la promotes GBM progression through SKP2 signaling, revealing SKP2 as a potential therapeutic target for disrupting hypoxia/necrosis-associated malignancy of GBM.