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. (February 2023)

• Record Type: Journal Article
• 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
• Is Part Of: Pharmacological research. Volume 188(2023)
• Publication Date: 2023-02
• Subjects: Phase separation -- Hepatocellular carcinoma -- Twist1-YY1-p300 complex -- MiR-9 -- Super-enhancer; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2023.106661
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: 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. Graphical Abstract: ga1