Transcriptional activation of SIRT6 via FKHRL1/FOXO3a inhibits the Warburg effect in glioblastoma cells

Glioblastoma (GBM) is the most aggressive and malignant form of brain tumors. However, its molecular mechanisms of tumorigenesis and cancer development remains to elucidate. Here, we reported FKHRL1, also called as FOXO3a, was an anti-cancer factor that inhibited the Warburg effect in GBM. Clinical data analysis revealed that FKHRL1 expression was positively correlated with the prognosis of patients with GBM. FKHRL1 silencing promoted glycolysis and cell growth of HEB gliocytes. Besides, FKHRL1 expression was tightly correlated with the expression of SIRT6 and a cluster of glycolytic genes that controlling the Warburg effect in glioma samples. Interestingly, the expression of SIRT6 was reduced after FKHRL1 knockdown, while its expression was upregulated when FKHRL1 was overexpressed in human U251 GBM cell line. In addition, SIRT6 restoration recovered the upregulated aerobic glycolysis induced by FKHRL1 knockdown. Meanwhile, SIRT6 knockdown also rescued the decrease of glucose metabolism induced by FKHRL1 overexpression. Luciferase assay and chromatin immunoprecipitation (ChIP) assay revealed that FKHRL1 bound to the promoter region of SIRT6 and enhanced its expression. Both in vitro and in vivo experiments further confirmed that FKHRL1-SIRT6 axis played a pivotal role in cell metabolism and tumor growth. Our results indicate that FKHRL1-SIRT6 axis regulates cell metabolism and may provide clues for GBM treatment.