Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-06605-1
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Funding
- Funding Program for NEXT Generation World-Leading Researchers (NEXT Program) from the Japan Society for the Promotion of Science (JSPS), Japan [LS071]
- program for Precursory Research for Embryonic Science and Technology (PRESTO) from the Japan Science and Technology Agency (JST)
- Japan Agency for Medical Research and development (AMED) [17ak0101084h0001]
- JSPS
- MEXT, Japan [26293276, 17H04261, 16H01640, 16H01573, 26461886, 17K10474, 15H06337, 17K16433, 26670558, 16K15576, 16K15577, 15K15454]
- research grant programs of the Princess Takamatsu Cancer Research Fund
- Takeda Science Foundation
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Suzuken Memorial Foundation
- Kobayashi Foundation for Cancer Research
- Tokyo Biochemical Research Foundation
- Japan China Medical Association
- Radiation Research Association, Japan
- Yasuda Medical Foundation
- Mitsui Life Social Welfare Foundation
- Grants-in-Aid for Scientific Research [16H01640, 26293276, 16H01573, 16K15576, 17H04261, 17H06812, 26670558, 15H05935, 15K15454, 16K15577, 17K16433, 26461886, 17K10474, 15H06337] Funding Source: KAKEN
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Hypoxia-inducible factor 1 (HIF-1) has been recognized as an important mediator of the reprogramming of carbohydrate metabolic pathways from oxidative phosphorylation to accelerated glycolysis. Although this reprogramming has been associated with the antioxidant and radioresistant properties of cancer cells, gene networks triggering the HIF-1-mediated reprogramming and molecular mechanisms linking the reprogramming with radioresistance remain to be determined. Here, we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1), which we previously identified as a novel HIF-1 activator, increased the radioresistance of cancer cells by producing an antioxidant, reduced glutathione (GSH), through HIF-1-mediated metabolic reprogramming. A luciferase assay to monitor HIF-1 activity demonstrated that the overexpression of UCHL1, but not its deubiquitination activity-deficient mutant (UCHL1 C90S), upregulated HIF-1 activity by stabilizing the regulatory subunit of HIF-1 (HIF-1 alpha) in a murine breast cancer cell line, EMT6. UCHL1 overexpression induced the reprogramming of carbohydrate metabolism and increased NADPH levels in a pentose phosphate pathway (PPP)-dependent manner. The UCHL1-mediated reprogramming elevated intracellular GSH levels, and consequently induced a radioresistant phenotype in a HIF-1-dependent manner. The pharmacological inhibition of PPP canceled the UCHL1-mediated radioresistance. These results collectively suggest that cancer cells acquire antioxidant and radioresistant phenotypes through UCHL1-HIF-1-mediated metabolic reprogramming including the activation of PPP and provide a rational basis for targeting this gene network for radiosensitization.
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