Hubei Key Laboratory of Cell Homeostasis , College of Life Sciences , Wuhan University , Wuhan , China.
Frontier Science Center for Immunology and Metabolism , Medical Research Institute , Wuhan University , Wuhan , China.
Hepatology. 2023 May 1;77(5):1499-1511. doi: 10.1002/hep.32518. Epub 2023 Apr 17.
Cholesterol ester (CE) biosynthesis and homeostasis play critical roles in many cancers, including HCC, but their exact mechanistic contributions to HCC disease development require further study.
Here, we report on a proposed role of tumor suppressor P53 in its repressing ubiquitin-specific peptidase 19 (USP19) and sterol O-acyltransferase (SOAT) 1, which maintains CE homeostasis. USP19 enhances cholesterol esterification and contributes to hepatocarcinogenesis (HCG) by deubiquitinating and stabilizing SOAT1. Loss of either SOAT1 or USP19 dramatically attenuates cholesterol esterification and HCG in P53-deficient mice fed with either a normal chow diet or a high-cholesterol, high-fat diet (HCHFD). SOAT1 inhibitor avasimibe has more inhibitory effect on HCC progression in HCHFD-maintained P53-deficient mice when compared to the inhibitors of de novo cholesterol synthesis. Consistent with our findings in the mouse model, the P53-USP19-SOAT1 signaling axis is also dysregulated in human HCCs.
Collectively, our findings demonstrate that SOAT1 participates in HCG by increasing cholesterol esterification, thus indicating that SOAT1 is a potential biomarker and therapeutic target in P53-deficient HCC.
胆固醇酯（CE）的生物合成和平衡在许多癌症中起着关键作用，包括 HCC，但它们对 HCC 疾病发展的确切机制贡献需要进一步研究。
在这里，我们报告了肿瘤抑制因子 P53 在抑制泛素特异性肽酶 19（USP19）和固醇 O-酰基转移酶 1（SOAT1）中的作用，SOAT1 维持 CE 平衡。USP19 通过去泛素化和稳定 SOAT1 增强胆固醇酯化作用，并有助于肝癌发生（HCG）。无论是缺失 SOAT1 还是 USP19，都会显著减弱 P53 缺陷小鼠的胆固醇酯化作用和 HCG，这些小鼠分别用正常饲料或高胆固醇高脂肪饮食（HCHFD）喂养。与从头合成胆固醇的抑制剂相比，在 HCHFD 维持的 P53 缺陷小鼠中，SOAT1 抑制剂 avasimibe 对 HCC 进展具有更强的抑制作用。与我们在小鼠模型中的发现一致，P53-USP19-SOAT1 信号轴在人类 HCC 中也失调。
综上所述，我们的研究结果表明，SOAT1 通过增加胆固醇酯化作用参与 HCG，因此表明 SOAT1 是 P53 缺陷 HCC 的潜在生物标志物和治疗靶点。
