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
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
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Twist1-YY1-p300复合物通过在超级增强子处形成相分离凝聚物激活miR-9促进HCC恶性进展并被二甲双胍缓解
DOI：
10.1016/j.phrs.2023.106661
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发表时间：
2023
影响因子：
9.3
通讯作者：
Tao Sun
中科院分区：
文献类型：
--
作者：
Jing Meng;Jingxia Han;Xiaorui Wang;Ting Wu;Heng Zhang;Huihui An;Luning Qin;Yu Sun;Weilong Zhong;Cheng Yang;Huijuan Liu;Tao Sun
肝细胞癌（Hepatocellular carcinoma，HCC）是导致人类死亡的主要原因之一，其发病机制有待进一步研究。研究表明，miR-9与HCC患者的不良预后相关。然而，miR-9的转录激活调控机制及其在HCC恶性进展中的作用很少被研究。一些转录辅激活因子可以在超级增强子处形成相分离的缩合物，所述超级增强子将转录装置区室化并集中以驱动稳健的基因表达。在这里，我们证明Twist 1和YY 1可以与p300形成转录复合物，在miR-9的超级增强子处产生局部高浓度相分离的相互作用枢纽，并激活其表达，通过刺激肝癌细胞的迁移和侵袭来促进HCC的恶性进展。Twist 1-YY 1-p300相分离的缩合物被二甲双胍（Met）破坏，从而降低miR-9表达，从而抑制HCC的恶性进展。我们的研究表明，Twist 1转录因子复合物参与了肝癌的恶性进展，可以在miR-9的超级增强子处形成相分离浓缩物，以促进肝癌细胞中癌基因的表达。它为肝癌的治疗提供了一个潜在的靶点，并为深入了解Met抑制肝癌的机制提供了线索。
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.