Twist1-YY1-p300 complex promotes the malignant progression of HCC through activation of miR-9 by forming phase-separated condensates at super-enhancers and relieved by metformin

• Published in: Pharmacological research 2023-02, Vol.188, p.106661-106661, Article 106661
• Main Authors: Meng, Jing, Han, Jingxia, Wang, Xiaorui, Wu, Ting, Zhang, Heng, An, Huihui, Qin, Luning, Sun, Yu, Zhong, Weilong, Yang, Cheng, Liu, Huijuan, Sun, Tao
• Format: Article
• Language: English
• Subjects: Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Metformin - pharmacology; Metformin - therapeutic use; MicroRNAs - genetics; MicroRNAs - metabolism; MiR-9; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phase separation; Super-enhancer; Twist-Related Protein 1 - genetics; Twist-Related Protein 1 - metabolism; Twist1-YY1-p300 complex; YY1 Transcription Factor - genetics; YY1 Transcription Factor - metabolism
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2023.106661

Hepatocellular carcinoma (HCC) is one of the leading causes of death, which deserves further study to reveal the underlying molecular mechanisms. Studies have shown that miR-9 in associated with poor prognosis in HCC patients. However, the mechanisms of transcriptional activation regulation of miR-9 and its role in the malignant progression of HCC have been rarely investigated. Some transcriptional coactivators can form phase-separated condensates at super-enhancers that compartmentalize and concentrate the transcription apparatus to drive robust gene expression. Here, we demonstrate that Twist1 and YY1 could form a transcriptional complex with p300, creating local high-concentration phase-separated interaction hubs at the super-enhancers of miR-9 and activate its expression to promote the malignant progression of HCC by stimulating the migration and invasion of hepatocellular carcinoma cells. Twist1-YY1-p300 phase-separated condensates were disrupted by metformin (Met) and thus reduce miR-9 expression, thereby inhibiting the malignant progression of HCC. Our study demonstrates that the Twist1 transcriptional factor complex involved in the malignant progression of HCC can form phase separation condensates at super-enhancers of miR-9 to promote the expression of oncogenes in HCC cells. It provides a potential target for the therapy of HCC and offers insights into the mechanism of Met in HCC inhibition. [Display omitted]