YY1 Complex Promotes Quaking Expression via Super-Enhancer Binding during EMT of Hepatocellular Carcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 7; pp. 1451 - 1464
• Main Authors: Han, Jingxia, Meng, Jing, Chen, Shuang, Wang, Xiaorui, Yin, Shan, Zhang, Qiang, Liu, Huijuan, Qin, Rong, Li, Zhongwei, Zhong, Weilong, Zhang, Chao, Zhang, Heng, Tang, Yuanhao, Lin, Tingting, Gao, Wanfeng, Zhang, Xiaoyun, Yang, Lan, Liu, Yanrong, Zhou, Hong-Gang, Sun, Tao, Yang, Cheng
• Format: Journal Article
• Language: English
• Published: United States 01.04.2019
• Subjects: Animals; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Enhancer Elements, Genetic; Epithelial-Mesenchymal Transition - drug effects; Humans; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis - prevention & control; Promoter Regions, Genetic; Protein Biosynthesis; Quercetin - analogs & derivatives; Quercetin - pharmacology; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Transcription, Genetic; YY1 Transcription Factor - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-2238

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 , 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 and . 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.