YY1 Complex Promotes Quaking Expression via Super-Enhancer Binding during EMT of Hepatocellular Carcinoma
YY1 Complex Promotes Quaking Expression via Super-Enhancer Binding during EMT of Hepatocellular Carcinoma
复制标题
YY1 复合物在肝细胞癌 EMT 过程中通过超级增强子结合促进 Quak 表达。
DOI：
10.1158/0008-5472.can-18-2238
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发表时间：
2019-04-01
期刊：
影响因子：
11.2
通讯作者：
Yang, Cheng
中科院分区：
文献类型：
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作者：
Han, Jingxia;Meng, Jing;Yang, Cheng
Quaking（QKI）是一种选择性剪接因子，在上皮-间充质转化过程中可调控circRNA的形成，但其机制尚不清楚。QKI的高表达与肝细胞癌（HCC）的生存时间短、转移、临床分期和病理分级高相关。本文报道了阴阳1（Yin-Yang 1，YY 1）/p65/p300复合物激活QKI基因的转录，其中YY 1与QKI的超级增强子和启动子结合，p65与启动子结合，p300作为介体维持复合物的稳定性。这种YY 1/p65/p300复合物增加了QKI的表达，从而促进了HCC的恶性程度，以及在体外和体内增加了circRNA的形成。金丝桃苷是几种植物源黄酮醇苷类化合物之一。通过虚拟筛选和抗肿瘤活性分析，我们发现金丝桃苷抑制QKI的表达是通过靶向YY 1/p65/p300复合物实现的。总体而言，我们的研究表明，QKI的调节机制依赖于YY 1/p65/p300复合物，它可能作为一个潜在的目标，为治疗HCC.Significance：这些研究结果确定了YY 1/p65/p300复合物作为QKI表达的调节器，确定了几个潜在的治疗肝癌的治疗靶点。
Quaking (QKI) is an alternative splicing factor that can regulate circRNA formation in the progression of epithelial-mesenchymal transition, but the mechanism remains unclear. High expression of QKI is correlated with short survival time, metastasis, and high clinical stage and pathology grade in hepatocellular carcinoma (HCC). Here we report that transcription of the QKI gene was activated by the Yin-Yang 1 (YY1)/p65/p300 complex, in which YY1 bound to the super-enhancer and promoter of QKI, p65 combined with the promoter, and p300 served as a mediator to maintain the stability of the complex. This YY1/p65/p300 complex increased QKI expression to promote the malignancy of HCC as well as an increased circRNA formation in vitro and in vivo. Hyperoside is one of several plant-derived flavonol glycoside compounds. Through virtual screening and antitumor activity analysis, we found that hyperoside inhibited QKI expression by targeting the YY1/p65/p300 complex. Overall, our study suggests that the regulatory mechanism of QKI depends on the YY1/p65/p300 complex and that it may serve as a potential target for treatment of HCC.Significance: These findings identify the YY1/p65/p300 complex as a regulator of QKI expression, identifying several potential therapeutic targets for the treatment of HCC.