Hypoxia-induced GBE1 expression promotes tumor progression through metabolic reprogramming in lung adenocarcinoma.

Lifeng Li, Li Yang, Zhirui Fan, Wenhua Xue, Zhibo Shen, Yongliang Yuan, Xiangdong Sun, Dan Wang, Jingyao Lian, Liping Wang, Jie Zhao, Yi Zhang

Signal transduction and targeted therapy 2020 May 22

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Hypoxia mediates a metabolic switch from oxidative phosphorylation to glycolysis and increases glycogen synthesis. We previously found that glycogen branching enzyme (GBE1) is downstream of the hypoxia-inducible factor-1 (HIF1) signaling pathway in lung adenocarcinoma (LUAD) cells; however, the molecular mechanism underlying HIF1 regulation of GBE1 expression remains unknown. Herein, the effect of GBE1 on tumor progression via changes in metabolic signaling under hypoxia in vitro and in vivo was evaluated, and GBE1-related genes from human specimens and data sets were analyzed. Hypoxia induced GBE1 upregulation in LUAD cells. GBE1-knockdown A549 cells showed impaired cell proliferation, clone formation, cell migration and invasion, angiogenesis, tumor growth, and metastasis. GBE1 mediated the metabolic reprogramming of LUAD cells. The expression of gluconeogenesis pathway molecules, especially fructose-1,6-bisphosphatase (FBP1), was markedly higher in shGBE1 A549 cells than it was in the control cells. FBP1 inhibited the tumor progression of LUAD. GBE1-mediated FBP1 suppression via promoter methylation enhanced HIF1α levels through NF-κB signaling. GBE1 may be a negative prognostic biomarker for LUAD patients. Altogether, hypoxia-induced HIF1α mediated GBE1 upregulation, suppressing FBP1 expression by promoter methylation via NF-κB signaling in LUAD cells. FBP1 blockade upregulated HIF1α, triggered the switch to anaerobic glycolysis, and enhanced glucose uptake. Therefore, targeting HIF1α/GBE1/NF-κB/FBP1 signaling may be a potential therapeutic strategy for LUAD.

Citation

Lifeng Li, Li Yang, Zhirui Fan, Wenhua Xue, Zhibo Shen, Yongliang Yuan, Xiangdong Sun, Dan Wang, Jingyao Lian, Liping Wang, Jie Zhao, Yi Zhang. Hypoxia-induced GBE1 expression promotes tumor progression through metabolic reprogramming in lung adenocarcinoma. Signal transduction and targeted therapy. 2020 May 22;5(1):54