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.

中文翻译：

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CYP46A1在人胶质母细胞瘤中的丢失介导的胆固醇稳态改变的治疗意义。

胆固醇代谢失调是包括胶质母细胞瘤（GBM）在内的许多癌症的标志，但人们对它在疾病进展中的作用还不甚了解。在这里，我们确定了胆固醇24-羟化酶（CYP46A1），这是一种大脑特异性酶，负责通过将胆固醇转化为24（S）-羟基胆固醇（24OHC）来消除胆固醇，是胆固醇中代谢异常严重的基因之一。 GBM。与正常脑组织相比，GBM样品中的CYP46A1显着降低。CYP46A1表达的减少与人类神经胶质瘤的肿瘤分级增加和预后不良有关。CYP46A1的异位表达通过增加24OHC水平来抑制细胞增殖和体内肿瘤的生长。RNA-seq显示，用24OHC处理GBM细胞可通过调节LXR和SREBP信号转导抑制肿瘤的生长。Efavirenz是一种已知的CYP46A1激活剂，可穿透血脑屏障，在体内抑制GBM的生长。我们的发现表明，CYP46A1是GBM中细胞胆固醇的关键调节剂，CYP46A1 / 24OHC轴是潜在的治疗靶标。