The oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to ferroptosis

Wang, Tianxiang; Liang, Jun-Yun; Zhang, Cheng; Xiong, Yue; Guan, Kun‐Liang; Yuan, Hai‐Xin

doi:10.1038/s41419-019-1984-4

Cited by 57 publications

(46 citation statements)

References 36 publications

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“…3C), prioritizing an innovative strategy to target IDH IDH1/2-mutant LGG. Supporting our nding, recent studies showed that accumulation of oncometabolite 2-hydroxyglutarate, the product of the mutant IDH, sensitizes cells to ferroptosis [23] and shRNA-based knockdown of IDH2 increases the sensitivity to Erastin-induced ferroptosis [24].…”

Section: Systematic Correlation Identi Es Cancer Drugs With the Potensupporting

confidence: 81%

Integrative pharmacogenomic profiling identifies novel cancer drugs and gene networks modulating ferroptosis sensitivity in pan-cancer

Yang¹,

Zhao²,

Yao³

et al. 2020

Preprint

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Background: Ferroptosis is an apoptosis-independent cell death program implicated in various diseases including cancer. Emerging evidence has demonstrated the promise of pharmacological induction of ferroptosis as a novel anti-cancer approach, but the molecular underpinnings of ferroptosis regulation and biomarkers associated with sensitivity to ferroptosis indcuers has been poorly defined. Methods: By implementing integrated pharmacogenomic analysis, we correlated the sensitivity of small-molecule compounds (n=481) against the transcriptomes of solid cancer cell lines (n=659). The potential of a drug compound to modulate ferroptosis was determined by significant (empirical p-value < 0.01) association of drug effectiveness with SLC7A11 expression. To establish generalized gene signatures for ferroptosis sensitivity and resistance, we interrogated drug effects of multiple ferroptosis inducers (n=7) with transcriptomic data of pan-solid cancer cells. Finally, the ferroptosis gene signature was applied to The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) project to identify cancer patients and cells that likely benefit from ferroptosis-based therapeutics. Results: We report, for the first time, the comprehensive identification of cancer drugs with the potential to induce ferroptosis and a generalized gene expression signature predicting ferroptosis response in pan-cancer. Informed by the findings, we reveal an unanticipated role for class I histone deacetylase (HDAC) in regulating ferroptosis and show that targeting HDAC significantly enhances the ferroptosis-promoting effect of Erastin in lung cancer cells. Moreover, our data indicate that small cell lung cancer (SCLC) and isocitrate dehydrogenase ( IDH )-mutant brain tumors are highly primed for ferroptosis, suggesting that relaunching ferroptosis might be an innovative strategy to target these malignancies. Conclusions: Expanding arsenal targeting aberrant ferroptosis and deciphering gene networks dictating ferroptosis sensitivity shed light on ferroptosis regulatory networks and may facilitate biomarker-guided stratification for ferroptosis-based therapy.

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Section: Systematic Correlation Identi Es Cancer Drugs With the Potensupporting

confidence: 81%

Integrative pharmacogenomic profiling identifies novel cancer drugs and gene networks modulating ferroptosis sensitivity in pan-cancer

Yang¹,

Zhao²,

Yao³

et al. 2020

Preprint

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“… 165 The sensitivity of ferroptosis is also affected by mutated epidermal growth factor receptor (EGFR) 78 or mutated IDH1. 166 Overall, the function of gene mutations in ferroptosis is context-sensitive.…”

Section: Implications Of Ferroptosis In Diseasementioning

confidence: 99%

Ferroptosis: molecular mechanisms and health implications

et al. 2020

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Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

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“…In IDH1 mutant, conversion of α-ketoglutarate to 2-hydroxyglutarate (2-HG) is reduced, and increases the 2-HG level in patients by 100 folds [12]. Accumulation of 2-HG suppresses cell growth and also induces ferroptosis [13]. In the IDH1 mutation group, cell-cycle-related genes are down-regulated in contrast to IDH1 wild-type group (Figure 3a, b).…”

Section: Discussionmentioning

confidence: 99%

Age-dependent Non-silent Somatic Mutation with Transcriptomic Landscape and Prognosis of Lower Grade Glioma

Park¹,

J²,

Jy³

et al. 2021

Preprint

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Glioma accounts for 80% of all malignant brain tumors and is the most common adult primary brain tumor. Age is an important factor affecting the development of cancer as somatic mutations accumulate with age. In this study, we aimed to analyze the significance of age-related non-silent somatic mutations in glioma prognosis. Histological tumor grade depends on age at diagnosis in patients with IDH1, TP53, ATRX, and EGFR mutations. The hierarchical clustering of patients was dominantly separated by IDH1 and EGFR mutations. Furthermore, patients with IDH1 mutation were dominantly separated by TP53 and ATRX double mutation and its double wildtype counterpart. Patients with the double mutation showed poorer prognosis than those with the double wild type genotype. In conclusion, among the many somatic mutations, those in IDH1, TP53, ATRX, and EGFR are important for glioma classification based on histological grade. Patients with EGFR mutation had the poorest prognosis, whereas those with only IDH1 mutation showed the best prognosis.

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The oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to ferroptosis

Cited by 57 publications

References 36 publications

Integrative pharmacogenomic profiling identifies novel cancer drugs and gene networks modulating ferroptosis sensitivity in pan-cancer

Integrative pharmacogenomic profiling identifies novel cancer drugs and gene networks modulating ferroptosis sensitivity in pan-cancer

Ferroptosis: molecular mechanisms and health implications

Age-dependent Non-silent Somatic Mutation with Transcriptomic Landscape and Prognosis of Lower Grade Glioma

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