A Both HIF1α and HIF2α had a positive relationship with Sox2 and Klf4. B There was a lower expression of Sox2 and Klf4 after knocking out HIF1α or HIF2α, and the levels were lowest after simultaneously knocking out HIF1α and HIF2α. C Compared with the control conditions, after knocking out Sox2 and Klf4, CD133 and CD15 expression decreased significantly. D The number of cells in the G1 phase decreased while the number of cells in the G2/M + S phase increased after knocking out Sox2 or Klf4. E After knocking out Sox2 or Klf4, the early, late and total apoptosis rates increased significantly compared with those in the control and empty vector cells. F HIF1α and HIF2α mutually regulate each other with negative feedback. HIF1α and HIF2α act as upstream gene regulators of EGF, and EGF regulates GBM malignancy through the EGFR–PI3K/AKT–mTOR–HIF1α signalling pathway. In addition, HIF1α and HIF2α upregulate Sox2 and Klf4 expression; high expression of Sox2 and Klf4 contributes to an increase in stemness expression and the transformation of cells in the G2/M + S phase to the G1 phase, thus leading to cell survival and therapy resistance. *P < 0.05 and #P > 0.05 were determined by one-way ANOVA.