Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma. Issue 1 (28th November 2019)

• Record Type: Journal Article
• Authors: Han, Mingzhi; Wang, Shuai; Yang, Ning; Wang, Xu; Zhao, Wenbo; Saed, Halala Sdik; Daubon, Thomas; Huang, Bin; Chen, Anjing; Li, Gang; Miletic, Hrvoje; Thorsen, Frits; Bjerkvig, Rolf; Li, Xingang; Wang, Jian
• Is Part Of: EMBO molecular medicine. Volume 12:Issue 1(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-11-28
• Subjects: 24OHC -- cholesterol homeostasis -- CYP46A1 -- efavirenz -- glioblastoma; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201910924
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: Loss of CYP46A1 partially caused excessive cholesterol accumulation in glioblastoma cells contributing to the maintenance of tumour cell viability and a malignant state. Efavirenz, an anti‐HIV drug, crosses the BBB and shows anti‐tumor effect though activation of the CYP46A1/24OHC axis. Loss of CYP46A1 promotes malignant behavior of GBM. CYP46A1 inhibits GBM cells growth via catalyzing the production of 24(S)‐hydroxycholesterol. Efavirenz, an anti‐HIV drug, has a a favorable BBB penetration. Drug repurposing of Efavirenz inhibits the growth of GBM via activation of the CYP46A1‐24OHC axis. Abstract : Loss of CYP46A1 partially caused excessive cholesterol accumulation in glioblastoma cells contributing to the maintenance of tumour cell viability and a malignant state. Efavirenz, an anti‐HIV drug, crosses the BBB and shows anti‐tumor effect though activation of the CYP46A1/24OHC axis.