The most well-characterized factor that controls DNA-PKcs kinase activity is the broken ends of DNA double-strand breaks (DSBs), which is generated either endogenously or exogenously . Binding to DNA initiates the activation of DNA-PKcs kinase. Once activated, DNA-PKcs kinase phosphorylates and alters the activity of proteins that mediate NHEJ involved in DNA damage response, including phosphorylating histone variant H2AX (γH2AX) at Ser139 either directly or indirectly through AKT/GSK3β signaling . In order to see if the hyperactivated DNA-PKcs was derived from DSBs, we investigated the expression of γH2AX in paired glioma samples using IHC. Our data revealed a poor correlation between p-DNA-PKcs and γH2AX, suggesting that activation of DNA-PKcs in glioma was not necessarily dependent on DSBs. Recently, growing evidences have characterized that, in addition to DSBs, several molecules might also perform as key modulators of DNA-PKcs activity in human cells. For example, Liccardi G et al. reported that nuclear translocated EGFR could bind to DNA-PKcs and enhance DNA-PKcs activity . Besides, Olsen BB et al. showed a critical role of protein kinase CK2 in DNA-PKcs activation in glioblastoma cells . Combined with these studies, our data that the upregulated p-DNA-PKcs levels in glioma samples did not correlate with DSB load indicated multiple underlying mechanisms might account for activation of DNA-PKcs in various tumors.