Abstract
Although the role of isocitrate dehydrogenase (IDH) mutation in promoting cancer development has been well-characterized, the impact of wild-type IDH on cancer cells remains unclear. Here we show that the wild-type isocitrate dehydrogenase 2 (IDH2) is highly expressed in colorectal cancer (CRC) cells, and plays an unexpected role in protecting the cancer cells from oxidative damage. Genetic abrogation of IDH2 in CRC cells leads to reactive oxygen species (ROS)-mediated DNA damage and an accumulation of 8-oxoguanine with DNA strand breaks, which activates DNA damage response (DDR) with elevated γH2AX and phosphorylation of ataxia telangiectasia-mutated (ATM) protein, leading to a partial cell cycle arrest and eventually cell senescence. Mechanistically, the suppression of IDH2 results in a reduction of the tricarboxylic acid (TCA) cycle activity due to a decrease in the conversion of isocitrate to α-ketoglutarate (α-KG) with a concurrent decrease in NADPH production, leading to ROS accumulation and oxidative DNA damage. Importantly, abrogation of IDH2 inhibits CRC cell growth in vitro and in vivo, and renders CRC cells more vulnerable to DNA-damaging drugs. Screening of an FDA-approved drug library has identified oxaliplatin as a compound highly effective against CRC cells when IDH2 was suppressed. Our study has uncovered an important role of the wild-type IDH2 in protecting DNA from oxidative damage, and provides a novel biochemical basis for developing metabolic intervention strategy for cancer treatment.
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Data availability
The datasets generated or analyzed for the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We would like to thank Yanyu Zhang, Mingquan Zhang and Bing-ling Luo for technical assistance, Haijing Deng and Dr. Hui Zhang for helpful discussions. Some of the cartoons in this article were created using the drawing tools provided by BioRender (https://biorender.com). This work was support in part by grants from the National Key R&D Program of China (2020YFA0803300, 2018YFC0910203), and from the National Natural Science Foundation of China (81872440, 81672952).
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SQ designed and performed research, analyzed data, and drafted paper. WL performed animal experiments. CG, PZ, NM, and HZ participated in bioinformatics analysis and biochemical/cellular experiments. JL participated in research design and paper writing. SW and PH designed the supervised the research. All authors have read and approved the final paper.
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Qiao, S., Lu, W., Glorieux, C. et al. Wild-type IDH2 protects nuclear DNA from oxidative damage and is a potential therapeutic target in colorectal cancer. Oncogene 40, 5880–5892 (2021). https://doi.org/10.1038/s41388-021-01968-2
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DOI: https://doi.org/10.1038/s41388-021-01968-2