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由SOX9和TCF7L2驱动的超强增强器重编程代表了用于治疗胆囊癌的转录向治疗脆弱性

Siyuan Yan^1,2, Zhaonan Liu^1,2, Teng Wang³

¹Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, P. R. China.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

|November 4, 2024

概括

研究人员确定了一种SOX9/TCF7L2调节环驱动胆囊癌 (GBC),并将其与预后不佳联系起来. 用CDK7抑制剂准这一循环显示出治疗GBC的前景.

科学领域:

表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.
癌症生物学癌症生物学
分子瘤学分子瘤学

背景情况:

胆囊癌 (GBC) 是一种具有有限向治疗的侵袭性恶性瘤.
超级增强剂 (SE) 是关键的表观遗传调节剂,与癌症发展有关.
在GBC中理解SE重编程对于确定治疗目标至关重要.

研究的目的:

调查超级增强剂 (SE) 和它们在胆囊癌 (GBC) 中的调节电路的作用.
确定驱动GBC中的瘤性SE重编程的关键转录因子 (TF).
探索针对已识别的SE驱动机制的潜在治疗策略.

主要方法:

在GBC组织和细胞系中分析H3K27ac分布,以映射SEs.
分析核心调节电路 (CRC) 以确定主转录因子 (TF).
在临床前模型中验证TF相互作用并评估CDK7抑制的治疗疗效.

主要成果:

确定了一个SOX9和TCF7L2自我调节循环,在GBC的一个子集中驱动瘤性SE重编程.
具有高SOX9/TCF7L2表达的GBC细胞显示对这些TFs的依赖以及干性,ErbB和Wnt通路基因的丰富.
较高的SOX9/TCF7L2高GBC细胞水平与患者预后明显恶化相关.
在临床前的GBC模型中,SOX9/TCF7L2过度表达对SE向的CDK7抑制有反应.

结论:

这项研究揭示了侵略性GBC的一个子集中的新型表观遗传机制.
SOX9/TCF7L2轴作为GBC的潜在预后生物标志物.
用CDK7抑制剂准SOX9/TCF7L2驱动的SE网络为GBC临床试验提供了一个有前途的治疗策略.

关键词:

这就是SOX9的SOX9.在TCF7L2中使用.核心调节电路的核心调节电路胆囊癌是一种胆囊癌.这是一个超级增强器.转录向的CDK7抑制疗法

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