Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma
Abstract 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 throu...
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| Language: | English |
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Springer Nature
2019-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201910924 |
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| author | Mingzhi Han Shuai Wang Ning Yang Xu Wang Wenbo Zhao Halala Sdik Saed Thomas Daubon Bin Huang Anjing Chen Gang Li Hrvoje Miletic Frits Thorsen Rolf Bjerkvig Xingang Li Jian Wang |
| author_facet | Mingzhi Han Shuai Wang Ning Yang Xu Wang Wenbo Zhao Halala Sdik Saed Thomas Daubon Bin Huang Anjing Chen Gang Li Hrvoje Miletic Frits Thorsen Rolf Bjerkvig Xingang Li Jian Wang |
| author_sort | Mingzhi Han |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-9027dbabbdc145e0a2567a88a9cc744f |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-9027dbabbdc145e0a2567a88a9cc744f2025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-11-0112111810.15252/emmm.201910924Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastomaMingzhi Han0Shuai Wang1Ning Yang2Xu Wang3Wenbo Zhao4Halala Sdik Saed5Thomas Daubon6Bin Huang7Anjing Chen8Gang Li9Hrvoje Miletic10Frits Thorsen11Rolf Bjerkvig12Xingang Li13Jian Wang14Shandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain‐Inspired Science, Shandong UniversityShandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain‐Inspired Science, Shandong UniversityShandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain‐Inspired Science, Shandong UniversityShandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain‐Inspired Science, Shandong UniversityShandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain‐Inspired Science, Shandong UniversityDepartment of Biomedicine, University of BergenINSERM U1029, Institut Nationale de la Santé et de la Recherche MédicaleShandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain‐Inspired Science, Shandong UniversityShandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain‐Inspired Science, Shandong UniversityShandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain‐Inspired Science, Shandong UniversityDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenShandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain‐Inspired Science, Shandong UniversityShandong Key Laboratory of Brain Function Remodeling, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain‐Inspired Science, Shandong UniversityAbstract 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.https://doi.org/10.15252/emmm.20191092424OHCcholesterol homeostasisCYP46A1efavirenzglioblastoma |
| spellingShingle | Mingzhi Han Shuai Wang Ning Yang Xu Wang Wenbo Zhao Halala Sdik Saed Thomas Daubon Bin Huang Anjing Chen Gang Li Hrvoje Miletic Frits Thorsen Rolf Bjerkvig Xingang Li Jian Wang Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma EMBO Molecular Medicine 24OHC cholesterol homeostasis CYP46A1 efavirenz glioblastoma |
| title | Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma |
| title_full | Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma |
| title_fullStr | Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma |
| title_full_unstemmed | Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma |
| title_short | Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma |
| title_sort | therapeutic implications of altered cholesterol homeostasis mediated by loss of cyp46a1 in human glioblastoma |
| topic | 24OHC cholesterol homeostasis CYP46A1 efavirenz glioblastoma |
| url | https://doi.org/10.15252/emmm.201910924 |
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