Cholesterol is essential for membrane biogenesis, cell proliferation, and differentiation. The role of cholesterol in cancer development and the regulation of cholesterol synthesis are still under active investigation. Here we show that under normal-sterol conditions, p53 directly represses the expression of SQLE, a rate-limiting and the first oxygenation enzyme in cholesterol synthesis, in a SREBP2-independent manner. Through transcriptional downregulation of SQLE, p53 represses cholesterol production in vivo and in vitro, leading to tumor growth suppression. Inhibition of SQLE using small interfering RNA (siRNA) or terbinafine (a SQLE inhibitor) reverses the increased cell proliferation caused by p53 deficiency. Conversely, SQLE overexpression or cholesterol addition promotes cell proliferation, particularly in p53 wild-type cells. More importantly, pharmacological inhibition or shRNA-mediated silencing of SQLE restricts nonalcoholic fatty liver disease (NAFLD)-induced liver tumorigenesis in p53 knockout mice. Therefore, our findings reveal a role for p53 in regulating SQLE and cholesterol biosynthesis, and further demonstrate that downregulation of SQLE is critical for p53-mediated tumor suppression.

中文翻译：

---

p53 转录调节 SQLE 以抑制胆固醇合成和肿瘤生长

胆固醇对膜生物发生、细胞增殖和分化至关重要。胆固醇在癌症发展中的作用和胆固醇合成的调节仍在积极研究中。在这里，我们表明在正常甾醇条件下，p53 以不依赖 SREBP2 的方式直接抑制 SQLE 的表达，SQLE 是胆固醇合成中的限速酶和第一个氧合酶。通过 SQLE 的转录下调，p53在体内和体外抑制胆固醇的产生，从而抑制肿瘤生长。使用小干扰 RNA (siRNA) 或特比萘芬（一种 SQLE 抑制剂）抑制 SQLE 可逆转由p53引起的细胞增殖增加不足。相反，SQLE 过表达或胆固醇添加会促进细胞增殖，尤其是在p53野生型细胞中。更重要的是，药理学抑制或 shRNA 介导的 SQLE 沉默限制了p53 基因敲除小鼠中非酒精性脂肪性肝病 (NAFLD) 诱导的肝肿瘤发生。因此，我们的研究结果揭示了 p53 在调节 SQLE 和胆固醇生物合成中的作用，并进一步证明 SQLE 的下调对于 p53 介导的肿瘤抑制至关重要。