Abstract
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 γ-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-1α (HIF-1α), a transcription factor that plays a role in hypoxia adaptation promoting aerobic glycolysis. In multiple human cancer cell lines, depletion of GGCT downregulated HIF-1α at the mRNA and protein levels. Conversely, in NIH3T3 mouse fibroblasts, overexpression of GGCT upregulated HIF-1α under normoxia. Moreover, depletion of GGCT downregulated HIF-1α 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-1α protein via the AMPK–mTORC1–4E-BP1 pathway in PC3 cells. Thus GGCT regulates the expression of HIF-1α in cancer cells, causing a switch to glycolysis.
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Acknowledgements
This work was supported by the Japan Society for the Promotion of Science, grant numbers 20K07623 and 16K08722; the Ministry of Education, Culture, Sports, Science and Technology–Supported Program for the Strategic Research Foundation at Private Universities 2015–2019; AMED Grant Number JP19nk0101386; the Takeda Science Foundation; and the Kyoto Pharmaceutical University Fund for the Promotion of Collaborative Research.
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KT performed most of the experiments, analyzed the data, and wrote the manuscript. S Kageyama and S Kubota performed the metabolome analysis. CM, SA, and HI performed some experiments. S Kageyama, EA, MH, TS, and AK supervised and designed experiments. SN designed the study, supervised the research, and wrote the manuscript. All authors reviewed the manuscript and accepted the final version.
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Taniguchi, K., Kageyama, S., Moyama, C. et al. γ-Glutamylcyclotransferase, a novel regulator of HIF-1α expression, triggers aerobic glycolysis. Cancer Gene Ther 29, 37–48 (2022). https://doi.org/10.1038/s41417-020-00287-0
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DOI: https://doi.org/10.1038/s41417-020-00287-0
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