YY1-EP300复合体通过促进SOAT1介导的胆固醇调节诱导肝癌EMT的机制研究

细胞中胆固醇代谢调控可直接影响多种细胞信号通路及生物过程，其代谢异常影响肿瘤发生及恶性进展。肝脏在体内胆固醇代谢平衡中发挥极重要作用。肝癌是世界上常见的高致死性恶性肿瘤，肝癌中胆固醇代谢出现病理性变化，但深入调控机制还需要进一步研究。SOAT1作为甾醇O-酰基转移酶，调节肝脏细胞胆固醇稳态，是新发现的一个重要的肝癌预后标志蛋白，但是其转录调控仍不清楚。在本研究中发现EMT的关键转录因子YY1、与染色质重塑调控转录的组蛋白乙酰转移酶EP300具有相互作用，而且在细胞核中有聚集成核斑点的相分离特征。因此在肝癌细胞中，因此我们猜测YY1-EP300复合体以相分离形式结合在SOAT1的超级增强子区域，极大地促进SOAT1的转录活性，调节胆固醇稳态促进肝癌EMT。相分离抑制剂的筛选突破单一蛋白结构的靶向药的限制。因此，针对肝癌胆固醇稳态调节的SOAT1的调控可为肝癌临床治疗提供新思路。

The regulation of cholesterol metabolism can directly affect many kinds of cell signaling pathways and biological processes, and its metabolic abnormalities affect tumor occurrence and malignant progress. Liver plays an important role in cholesterol metabolism. Hepatocellular carcinoma (HCC) is a common highly lethal malignant tumor, which pathological changes exists in cholesterol metabolism. But further research is needed in the regulation mechanism. As a Sterol O-Acyltransferase, SOAT1 regulates cholesterol homeostasis in liver cells, which is a new and important prognostic marker protein for HCC, but its transcriptional regulation is still unclear. In this study, we found that YY1, the key transcription factor of EMT, interacted with histone acetyltransferase EP300, which regulates transcription by chromatin remodeling, and had the characteristics of phase separation in the nucleus. Therefore, in hepatoma cells, we speculate that YY1-EP300 complex is bound in the super enhancer region of SOAT1 in the form of phase separation, which greatly promotes the transcription activity of SOAT1, regulates cholesterol homeostasis and promotes EMT. The screening of phase separation inhibitors breaks through the limitation of single protein structure targeting drugs, and has pertinence. Therefore, the study of the regulation of SOAT1 in the cholesterol homeostasis of HCC can provide new insight for the clinical treatment of HCC.