دورية أكاديمية
أعرض في EDS

Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma.

التفاصيل البيبلوغرافية
العنوان: Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma.
المؤلفون: Han M; Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.; Department of Biomedicine, University of Bergen, Bergen, Norway., Wang S; Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China., Yang N; Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China., Wang X; Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China., Zhao W; Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China., Saed HS; Department of Biomedicine, University of Bergen, Bergen, Norway., Daubon T; INSERM U1029, Institut Nationale de la Santé et de la Recherche Médicale, Pessac, France.; University Bordeaux, Pessac, France., Huang B; Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China., Chen A; Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.; School of Medicine, Shandong University, Jinan, China., Li G; Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China., Miletic H; Department of Biomedicine, University of Bergen, Bergen, Norway.; Department of Pathology, Haukeland University Hospital, Bergen, Norway., Thorsen F; Department of Biomedicine, University of Bergen, Bergen, Norway.; Department of Biomedicine, The Molecular Imaging Center, University of Bergen, Bergen, Norway., Bjerkvig R; Department of Biomedicine, University of Bergen, Bergen, Norway.; NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg., Li X; Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China., Wang J; Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.; Department of Biomedicine, University of Bergen, Bergen, Norway.
المصدر: EMBO molecular medicine [EMBO Mol Med] 2020 Jan 09; Vol. 12 (1), pp. e10924. Date of Electronic Publication: 2019 Nov 28.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101487380 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1757-4684 (Electronic) Linking ISSN: 17574676 NLM ISO Abbreviation: EMBO Mol Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Chichester, West Sussex : Wiley-Blackwell
مواضيع طبية MeSH: Cholesterol 24-Hydroxylase*/genetics , Cholesterol 24-Hydroxylase*/metabolism , Glioblastoma*/metabolism, Cholesterol/*metabolism, Brain/metabolism ; Homeostasis ; Humans
مستخلص: Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for the elimination of cholesterol through the conversion of cholesterol into 24(S)-hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. CYP46A1 was significantly decreased in GBM samples compared with normal brain tissue. A reduction in CYP46A1 expression was associated with increasing tumour grade and poor prognosis in human gliomas. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. RNA-seq revealed that treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz, an activator of CYP46A1 that is known to penetrate the blood-brain barrier, inhibited GBM growth in vivo. Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target.
(© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)
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معلومات مُعتمدة: 2017CXGC1502 International Department of Science & Technology of Shandong Province; 2018CXGC1503 International Department of Science & Technology of Shandong Province; 2018GSF118082 International Department of Science & Technology of Shandong Province; ts20110814 International Special Foundation for Taishan Scholars; tshw201502056 International Special Foundation for Taishan Scholars; ts201511093 International Special Foundation for Taishan Scholars; 201704096 International Jinan Science and Technology Bureau of Shandong Province; 81972351 International National Natural Science Foundation of China; 81702474 International National Natural Science Foundation of China; 81702475 International National Natural Science Foundation of China; ZR2017MH116 International Shandong Provincial Natural Science Foundation; 2018M642666 International China Postdoctoral Science Foundation; KF-182701 International Norwegian Cancer Society; ES563961 International Norwegian Research Council; International Haukeland University Hospital; 990069 International Helse-Vest; International University of Bergen
فهرسة مساهمة: Keywords: 24OHC; CYP46A1; cholesterol homeostasis; efavirenz; glioblastoma
سلسلة جزيئية: GEO GSE54047; GSE46016; GSE46014
المشرفين على المادة: 97C5T2UQ7J (Cholesterol)
EC 1.14.14.25 (Cholesterol 24-Hydroxylase)
تواريخ الأحداث: Date Created: 20191129 Date Completed: 20210727 Latest Revision: 20240327
رمز التحديث: 20240327
مُعرف محوري في PubMed: PMC6949512
DOI: 10.15252/emmm.201910924
PMID: 31777202
قاعدة البيانات: MEDLINE
الوصف
تدمد:1757-4684
DOI:10.15252/emmm.201910924