@article{37a7766a979a4c8db9bfda714dcf1db8,
title = "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 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.",
keywords = "24OHC, CYP46A1, cholesterol homeostasis, efavirenz, glioblastoma",
author = "Mingzhi Han and Shuai Wang and Ning Yang and Xu Wang and Wenbo Zhao and Saed, {Halala Sdik} and Thomas Daubon and Bin Huang and Anjing Chen and Gang Li and Hrvoje Miletic and Frits Thorsen and Rolf Bjerkvig and Xingang Li and Jian Wang",
note = "Funding Information: We thank Dr. Justin Vareecal Joseph for establishing and providing primary GBM cells. This work was supported by the National Natural Science Foundation of China (81972351, 81702474 and 81702475), the Department of Science & Technology of Shandong Province (2017CXGC1502, 2018CXGC1503 and 2018GSF118082), the Special Foundation for Taishan Scholars (ts20110814, tshw201502056 and ts201511093), the Shandong Provincial Natural Science Foundation (ZR2017MH116), the China Postdoctoral Science Foundation (2018M642666), the Jinan Science and Technology Bureau of Shandong Province (201704096), the Norwegian Cancer Society, the Norwegian Research Council (ES563961), Haukeland University Hospital, Helse‐Vest and the University of Bergen. Funding Information: We thank Dr. Justin Vareecal Joseph for establishing and providing primary GBM cells. This work was supported by the National Natural Science Foundation of China (81972351, 81702474 and 81702475), the Department of Science & Technology of Shandong Province (2017CXGC1502, 2018CXGC1503 and 2018GSF118082), the Special Foundation for Taishan Scholars (ts20110814, tshw201502056 and ts201511093), the Shandong Provincial Natural Science Foundation (ZR2017MH116), the China Postdoctoral Science Foundation (2018M642666), the Jinan Science and Technology Bureau of Shandong Province (201704096), the Norwegian Cancer Society, the Norwegian Research Council (ES563961), Haukeland University Hospital, Helse-Vest and the University of Bergen. Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2020",
month = jan,
day = "9",
doi = "10.15252/emmm.201910924",
language = "English",
volume = "12",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "1",
}