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Isocitrate dehydrogenase 1 mutation enhances 24(S)-hydroxycholesterol production and alters cholesterol homeostasis in glioma

Oncogene volume 39, pages 6340–6353 (2020)Cite this article

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Abstract

Isocitrate dehydrogenase (IDH) mutation is the most important initiating event in gliomagenesis, and the increasing evidence shows that IDH mutation is associated with the metabolic reprogramming in the tumor. Dysregulated cholesterol metabolism is a hallmark of tumor cells, but the cholesterol homeostasis in IDH-mutated glioma is still unknown. In this study, we found that astrocyte-specific mutant IDH1(R132H) knockin reduced the cholesterol contents and damaged the structure of myelin in mouse brains. In U87 and U251 cells, the expression of mutant IDH1 consistently reduced the cholesterol levels. Furthermore, we found that IDH1 mutation enhanced the production of 24(S)-hydroxycholesterol (24-OHC), which is not only the metabolite of cholesterol elimination, but also functions as an endogenous ligand for the liver X receptors (LXRs). In IDH1-mutant glioma cells, the elevated 24-OHC activated LXRs, which consequently accelerated the low-density lipoprotein receptor (LDLR) degradation by upregulating the inducible degrader of the LDLR (IDOL). The reduced LDLR expressions in IDH1-mutant glioma cells abated the uptakes of low-density lipoprotein (LDL) to decrease the cholesterol influx. In addition, the activated LXRs also promoted the cholesterol efflux by elevating the ATP-binding cassette transporter A1 (ABCA1), ABCG1, and apolipoprotein E (ApoE) in both IDH1-mutant astrocytes and glioma cells. As a feedback, the reduced cholesterol levels stimulated the cholesterol biosynthesis, which made IDH1-mutated glioma cells more sensitive to atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase. The altered cholesterol homeostasis regulated by mutant IDH provides a pivotal therapeutical strategy for the IDH-mutated gliomas.

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Fig. 1: IDH1 mutation lowered cholesterol contents in the mouse brain and glioma cells.
Fig. 2: IDH1 mutation promoted the production of 24-OHC in glioma cells.
Fig. 3: IDH1 mutation accelerated LDLR degradation in glioma cells.
Fig. 4: IDH1 mutation impeded the LDL uptake in glioma cells.
Fig. 5: IDH1 mutation promoted cholesterol efflux in both primary astrocytes and glioma cells.
Fig. 6: IDH1 mutation stimulated cholesterol biosynthesis in astrocytes and glioma cells.

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Acknowledgements

The research work was supported by the National Natural Science Foundation of China (81972342, 81772659 to JY, 81670792 to LZ), State Key Laboratory of Cancer Biology of China (CBSKL2017Z20 to YG), and Natural Science Basic Research Plan in Shaanxi Province (2020JZ-29 to JY, 2020JQ-462 to XG).

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  1. These authors contributed equally: Risheng Yang, Yuanlin Zhao, Yu Gu

Authors and Affiliations

  1. State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi’an, Shaanxi, China

    Risheng Yang, Yuanlin Zhao, Yu Gu, Ying Yang, Xing Gao, Yuan Yuan, Liming Xiao, Han Yang, Junhui Qin, Jing Li, Feng Zhang & Jing Ye

  2. Institude of Cancer, Xinqiao Hospital, Army Medical University, 400037, Chongqing, China

    Jin Zhang

  3. Department of Neurology, Tangdu Hospital, Fourth Military Medical University, 710038, Xi’an, Shaanxi, China

    Chao Sun

  4. Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, 710038, Xi’an, Shaanxi, China

    Lijun Zhang

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Contributions

RY designed, oversaw all and performed most of experiments, and wrote the manuscript; YZ conceived and performed the experiments; YYang, XG, YYuan, LX, YG, JZ, CS, and HY provided research materials and methods; YG, JQ, JL, and FZ provided clinical supports; LZ and JY developed the concept of the study, and edited the manuscript. All authors read and approved the final paper.

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Yang, R., Zhao, Y., Gu, Y. et al. Isocitrate dehydrogenase 1 mutation enhances 24(S)-hydroxycholesterol production and alters cholesterol homeostasis in glioma. Oncogene 39, 6340–6353 (2020). https://doi.org/10.1038/s41388-020-01439-0

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