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

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

Oncogene (2020-08-29)
Risheng Yang, Yuanlin Zhao, Yu Gu, Ying Yang, Xing Gao, Yuan Yuan, Liming Xiao, Jin Zhang, Chao Sun, Han Yang, Junhui Qin, Jing Li, Feng Zhang, Lijun Zhang, Jing Ye
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.

MATERIALS
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Product Description

Sigma-Aldrich
Crystal Violet, certified by the Biological Stain Commission
Supelco
Atorvastatin Calcium, Pharmaceutical Secondary Standard; Certified Reference Material