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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.

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
Source :
Pharmacological Research. Feb2023, Vol. 188, pN.PAG-N.PAG. 1p.
Publication Year :
2023

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. [Display omitted] [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
10436618
Volume :
188
Database :
Academic Search Index
Journal :
Pharmacological Research
Publication Type :
Academic Journal
Accession number :
161767631
Full Text :
https://doi.org/10.1016/j.phrs.2023.106661