Target identification reveals lanosterol synthase as a vulnerability in glioma

Phillips, Richard E.; Yang, Yanhong; Smith, R. V.; Thompson, Bonne M.; Yamasaki, Tomoko; Soto‐Feliciano, Yadira M.; Funato, Kosuke; Liang, Yupu; García‐Bermúdez, Javier; Wang, Xiaoshi; García, Benjamin A.; Yamasaki, Kazuhiko; McDonald, Jeffrey G.; Birsoy, Kıvanç; Tabar, Viviane; Allis, C. David

doi:10.1073/pnas.1820989116

Cited by 56 publications

(34 citation statements)

References 46 publications

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“…Sterol products can activate RORC signalling [26], promote oligodendrocyte formation [57], or activate LXRα and inhibit EGFR signalling [58]. Inhibitors of lanosterol synthase were identified as potential anticancer drug targets [59] while the accumulation of lanosterol can cause degradation of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) [60]. Our sterol measurements show significant accumulation of CYP51A1 substrates lanosterol and dihydrolanosterol, with no sex differences.…”

Section: Discussionmentioning

confidence: 83%

Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer

Cokan

Urlep

Lorbek

et al. 2020

Cancers

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While the role of cholesterol in liver carcinogenesis remains controversial, hepatocellular carcinoma generally prevails in males. Herein, we uncover pathways of female-prevalent progression to hepatocellular carcinoma due to chronic repression of cholesterogenic lanosterol 14α-demethylase (CYP51) in hepatocytes. Tumors develop in knock-out mice after year one, with 2:1 prevalence in females. Metabolic and transcription factor networks were deduced from the liver transcriptome data, combined by sterol metabolite and blood parameter analyses, and interpreted with relevance to humans. Female knock-outs show increased plasma cholesterol and HDL, dampened lipid-related transcription factors FXR, LXRα:RXRα, and importantly, crosstalk between reduced LXRα and activated TGF-β signalling, indicating a higher susceptibility to HCC in aging females. PI3K/Akt signalling and ECM-receptor interaction are common pathways that are disturbed by sex-specific altered genes. Additionally, transcription factors (SOX9)2 and PPARα were recognized as important for female hepatocarcinogenesis, while overexpressed Cd36, a target of nuclear receptor RORC, is a new male-related regulator of ECM-receptor signalling in hepatocarcinogenesis. In conclusion, we uncover the sex-dependent metabolic reprogramming of cholesterol-related pathways that predispose for hepatocarcinogenesis in aging females. This is important in light of increased incidence of liver cancers in post-menopausal women.

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Section: Discussionmentioning

confidence: 83%

Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer

Cokan

Urlep

Lorbek

et al. 2020

Cancers

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“…The result of survival analysis shows that LSS in metabolic subpathway 00100_6 plays a significant role in the prognosis of GBM patients (HR = 1.5) ( Figure 3D ). LSS has also been proved to have a significant effect on GBM and may be a potential therapeutic target ( 36 , 37 ). These results indicate that LSS may be a key gene of metabolic subpathway 00100_6.…”

Section: Resultsmentioning

confidence: 99%

Inference of Subpathway Activity Profiles Reveals Metabolism Abnormal Subpathway Regions in Glioblastoma Multiforme

et al. 2020

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Glioblastoma, also known as glioblastoma multiforme (GBM), is the most malignant form of glioma and represents 81% of malignant brain and central nervous system (CNS) tumors. Like most cancers, GBM causes metabolic recombination to promote cell survival, proliferation, and invasion of cancer cells. In this study, we propose a method for constructing the metabolic subpathway activity score matrix to accurately identify abnormal targets of GBM metabolism. By integrating gene expression data from different sequencing methods, our method identified 25 metabolic subpathways that were significantly abnormal in the GBM patient population, and most of these subpathways have been reported to have an effect on GBM. Through the analysis of 25 GBM-related metabolic subpathways, we found that (S)-2,3-Epoxysqualene, which was at the central region of the sterol biosynthesis subpathway, may have a greater impact on the entire pathway, suggesting a potential high association with GBM. Analysis of CCK8 cell activity indicated that (S)-2,3-Epoxysqualene can indeed inhibit the activity of U87-MG cells. By flow cytometry, we demonstrated that (S)-2,3-Epoxysqualene not only arrested the U87-MG cell cycle in the G0/G1 phase but also induced cell apoptosis. These results confirm the reliability of our proposed metabolic subpathway identification method and suggest that (S)-2,3-Epoxysqualene has potential therapeutic value for GBM. In order to make the method more broadly applicable, we have developed an R system package crmSubpathway to perform disease-related metabolic subpathway identification and it is freely available on the GitHub ( https://github.com/hanjunwei-lab/crmSubpathway ).

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“…The menin inhibitor, MI‐2 was identified as a top hit in a drug screen for growth inhibition of tumour‐competent H3K27M, PDGFRA D842V expressing p53 knockdown hNPCs compared to normal NPCs, but the lack of mutations in menin or its binding partner MLL1 in gliomas was puzzling . A recent study determined that in glioma cells, MI‐2 acts via a menin‐independent mechanism and instead disrupts cholesterol homoeostasis by targeting lanosterol synthase .…”

Section: Therapeutic Outlookmentioning

confidence: 99%

Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

Kasper

Baker

2020

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 73-85 Emerging functions of histone H3 mutations in paediatric diffuse high-grade gliomas Paediatric diffuse high-grade gliomas (pHGG) are rare, but deadly tumours. The discovery of recurrent mutations in the tail of histone H3, changing lysine 27 to methionine, or glycine 34 to arginine or valine, has illuminated a critical role for epigenetic dysregulation in the aetiology of childhood gliomas and opened new avenues of exploration that have resulted in numerous advances for the field. In this review, we describe the current models of H3K27M mutant cancer that are available to the research community and the insights they have provided on tumour biology and the epigenetic and transcriptional effects of histone mutations. We also review the current understanding of the H3G34R/V mutation and the therapeutic outlook for the treatment of pHGG.

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Target identification reveals lanosterol synthase as a vulnerability in glioma

Cited by 56 publications

References 46 publications

Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer

Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer

Inference of Subpathway Activity Profiles Reveals Metabolism Abnormal Subpathway Regions in Glioblastoma Multiforme

Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

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