γ-Glutamylcyclotransferase, a novel regulator of HIF-1α expression, triggers aerobic glycolysis
γ-Glutamylcyclotransferase, a novel regulator of HIF-1α expression, triggers aerobic glycolysis
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DOI：
10.1038/s41417-020-00287-0
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发表时间：
2021-01-05
影响因子：
6.4
通讯作者：
Nakata, Susumu
中科院分区：
文献类型：
--
作者：
Taniguchi, Keiko;Kageyama, Susumu;Nakata, Susumu
代谢重编程导致有氧糖酵解，称为“瓦尔堡效应”，是癌细胞的一个关键特性。然而，这种现象背后的确切机制尚未完全了解。越来越多的证据表明，γ-谷氨酰环转移酶（GGCT），一种参与谷胱甘肽体内平衡的酶，在许多类型的癌症中高度表达，代表了一个有前途的治疗靶点。在这项研究中，我们确定GGCT作为缺氧诱导因子-1 α（HIF-1 α）的一种新的调节因子，HIF-1 α是一种转录因子，在促进有氧糖酵解的缺氧适应中发挥作用。在多种人类癌细胞系中，GGCT的耗竭在mRNA和蛋白水平下调HIF-1 α。相反，在NIH 3 T3小鼠成纤维细胞中，GGCT的过表达在常氧下上调HIF-1 α。此外，GGCT的缺失会下调参与糖酵解的HIF-1 α下游靶基因，而GGCT的过表达会上调这些基因。代谢组学分析表明，GGCT表达的调制诱导代谢开关从柠檬酸循环糖酵解下常氧。此外，我们发现GGCT通过AMPK-mTORC 1 - 4 E-BP 1途径调节PC 3细胞中HIF-1 α蛋白的表达。因此，GGCT调节癌细胞中HIF-1 α的表达，导致糖酵解的转变。
Metabolic reprogramming leading to aerobic glycolysis, termed the "Warburg effect," is a critical property of cancer cells. However, the precise mechanisms underlying this phenomenon are not fully understood. A growing body of evidence indicates that gamma-glutamylcyclotransferase (GGCT), an enzyme involved in glutathione homeostasis that is highly expressed in many types of cancer, represents a promising therapeutic target. In this study, we identified GGCT as a novel regulator of hypoxia-inducible factor-1 alpha (HIF-1 alpha), a transcription factor that plays a role in hypoxia adaptation promoting aerobic glycolysis. In multiple human cancer cell lines, depletion of GGCT downregulated HIF-1 alpha at the mRNA and protein levels. Conversely, in NIH3T3 mouse fibroblasts, overexpression of GGCT upregulated HIF-1 alpha under normoxia. Moreover, depletion of GGCT downregulated HIF-1 alpha downstream target genes involved in glycolysis, whereas overexpression of GGCT upregulated those genes. Metabolomic analysis revealed that modulation of GGCT expression induced a metabolic switch from the citric acid cycle to glycolysis under normoxia. In addition, we found that GGCT regulates expression of HIF-1 alpha protein via the AMPK-mTORC1-4E-BP1 pathway in PC3 cells. Thus GGCT regulates the expression of HIF-1 alpha in cancer cells, causing a switch to glycolysis.