FSMP-11. TARGETING CHOLESTEROL HOMEOSTASIS DYSREGULATION FOR THE TREATMENT OF GLIOBLASTOMA

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 elimination of cholesterol through conversion of cholesterol to 24(S)-hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. CYP46A1 was significantly decreased in GBM samples compared to normal brain tissue. In gliomas, a reduction in CYP46A1 expression was associated with increasing tumour grade and poor prognosis. Functionally, 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 signaling. Efavirenz (EFV), an activator of CYP46A1 that is known to penetrate the blood-brain barrier (BBB), 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.