State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing 400716, China; Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing 400716, China; Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing 400716, China; Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing 400716, China.
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Cell Signal. 2019 Aug;60:100-113. doi: 10.1016/j.cellsig.2019.04.009. Epub 2019 Apr 17.
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.
胶质母细胞瘤（GBM）是最具侵袭性和恶性的脑肿瘤。然而，其肿瘤发生和癌症发展的分子机制仍需阐明。在这里，我们报道了 FKHRL1，也称为 FOXO3a，是一种抗癌因子，可抑制 GBM 中的瓦博格效应。临床数据分析表明，FKHRL1 的表达与 GBM 患者的预后呈正相关。FKHRL1 沉默促进了 HEB 神经胶质瘤细胞的糖酵解和细胞生长。此外，FKHRL1 的表达与 SIRT6 的表达以及一组控制神经胶质瘤样本中瓦博格效应的糖酵解基因紧密相关。有趣的是，在 FKHRL1 敲低后，SIRT6 的表达减少，而在人 U251 GBM 细胞系中过表达 FKHRL1 时，其表达上调。此外，SIRT6 的恢复恢复了 FKHRL1 敲低诱导的有氧糖酵解的上调。同时，SIRT6 的敲低也挽救了 FKHRL1 过表达诱导的葡萄糖代谢减少。萤光素酶测定和染色质免疫沉淀（ChIP）测定表明，FKHRL1 结合到 SIRT6 的启动子区域并增强其表达。体内外实验进一步证实，FKHRL1-SIRT6 轴在细胞代谢和肿瘤生长中起着关键作用。我们的结果表明，FKHRL1-SIRT6 轴调节细胞代谢，并可为 GBM 的治疗提供线索。
