| Glioblastoma(GBM)is the most common and invasive primary brain tumor with high malignancy,recurrence rate and mortality after treatment.Glioma stem cells(GSCs),a GBM cell subpopulation with self-renewal and multi-lineage differentiation potential,promote the invasiveness and chemoradioresistance of GBM,and thus are crucial targets for the treatment of GBM.GBM is more prone to use aerobic glycolysis to provide energy for cells,which is called "Warburg effect".As a result,the end product of aerobic glycolysis,lactate,is dramatically elevated in GBM cells and act as substrates for post-translational modification-lysine lactylation(Kla).Lactylation has been reported to be closely related to the occurrence and development of tumors.However,it is not clear whether GBM has abnormal lactylation and whether lactylation promotes the malignant development of GBM.Here,we showed that lactylation was elevated in GBM,especially in GSCs.Further analysis showed that GSCs had high glycolysis level and high expression of lactate transporter MCT1 and lactylation writer EP300,which may be the reason for the high level of lactylation of GSCs.In vitro,lactate treatment could significantly improve the lactylation level in GSCs and promote GSCs migration,invasion and radioresistance.On the other hand,using oxamate or 2-DG could significantly reduce the lactylation of GSCs and inhibit their migration,invasion and radioresistance.To explore the mechanism of high lactylation promoting GSCs migration,invasion and radioresistance,we performed immunoprecipitation assay to obtain lactylated proteins and analyzed the proteins by mass spectrometry.The results showed that thirty-nine proteins were found with specific lactylation in GSCs.After functional annotation of these target proteins,we speculated that these proteins may be closely related to tumorigenesis,and some proteins may be directly involved in the invasion and radioresistance of GBM which need validations in our future study.In summary,this project reveals the oncogenic role of high lactylation in GSCs,which may provide new therapeutic targets for GBM. |
