四川大学姜昊团队的一项最新研究发现了靶向TFAP2β缩合抑制食管鳞状细胞癌的发展。这一研究成果发表在2025年12月16日出版的国际学术期刊《细胞》上。
在对有限数量临床样本的转座酶可及染色质主题测序（ATAC-seq）方案进行改进后，研究团队通过结合对早期ESCC患者癌组织和癌旁组织的染色质可及性和基因表达分析，揭示了转录因子AP-2 β (TFAP2β)是一个关键的下调转录因子（TF）。TFAP2β在核胞中通过缩合结合锌指蛋白131 （ZNF131）启动子，从而抑制ZNF131的表达和ESCC的进展。发现的另外两个重要的下调TFs被结合到TFAP2β凝聚物中以结合相应的靶标，这表明LLPS可能是ESCC转录的标志。此外，小组获得了介导内在无序区域构象变化的化合物A6，以增强细胞、小鼠和患者来源的类器官中TFAP2β的凝聚和特异性ESCC抑制。因此，该课题组人员指出了LLPS介导的转录机制和ESCC的潜在治疗方法。
据悉，探索食管鳞状细胞癌（ESCC）的靶向治疗仍然具有挑战性。尽管研究液-液相分离（LLPS）的作用和治疗应用越来越受到关注，但其与ESCC的关系尚不清楚。
附：英文原文
Title: Targeting TFAP2β condensation suppresses the development of esophageal squamous cell carcinoma
Author: Zhaomin Deng, Lu Pu, Kai Deng, Wencheng Liu, Jifa Zhang, Liang Zhang, Qian Meng, Wanwan Zhou, Haoran Jin, Dongqin Xu, Shaochong Qi, Zhihan Wu, Yongxin Ma, Xing Liu, Xuebiao Yao, Bowen Ke, David J. Kerr, Li Yang, Jinlin Yang, Hao Jiang
Issue&Volume: 2025-12-16
Abstract: Exploring targeted therapies for esophageal squamous cell carcinoma (ESCC) remains challenging. Although investigating the roles and therapeutic applications of liquid-liquid phase separation (LLPS) is increasingly of interest, its relationship with ESCC remains unclear. After improving the assay for transposase-accessible chromatin using sequencing (ATAC-seq) protocol for limited-amount clinical samples, we unravel transcription factor AP-2 beta (TFAP2β) as a key downregulated transcription factor (TF) through combined chromatin accessibility and gene expression analyses with cancerous and paracancerous tissues from early-stage ESCC patients. TFAP2β undergoes condensation in the nucleus to bind the zinc finger protein 131 (ZNF131) promoter, thereby inhibiting ZNF131 expression and ESCC progression. The other two crucial downregulated TFs uncovered are incorporated into TFAP2β condensates to bind their corresponding target, suggesting that LLPS may be a hallmark of ESCC transcription. In addition, we obtained compound A6 that mediates intrinsically disordered region conformational changes to enhance TFAP2β condensation and specific ESCC suppression in cells, mice, and patient-derived organoids. Thus, we indicate an LLPS-mediated transcriptional mechanism and a potential therapeutic approach for ESCC.
DOI: 10.1016/j.cell.2025.11.019
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01315-7