Targeting TFAP2β condensation suppresses the development of esophageal squamous cell carcinoma

Zhaomin Deng¹, Lu Pu², Kai Deng³, Wencheng Liu⁴, Jifa Zhang⁵, Liang Zhang⁶, Qian Meng⁷, Wanwan Zhou⁸, Haoran Jin³, Dongqin Xu², Shaochong Qi⁹, Zhihan Wu³, Yongxin Ma¹⁰, Xing Liu⁸, Xuebiao Yao⁸, Bowen Ke¹¹, David J Kerr¹², Li Yang¹³, Jinlin Yang¹⁴, Hao Jiang¹⁵

Affiliations

¹ Laboratory of Aging and Cancer, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Medical Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
² Laboratory of Aging and Cancer, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Aging and Cancer, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
³ Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
⁴ Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
⁵ Department of Neurology, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, China.
⁶ Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Cross-Disciplinary Science, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; School of Synthetic Biology and Biomanufacturing, Tianjin University, Tianjin 300072, China.
⁷ Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁸ Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Cross-Disciplinary Science, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
⁹ The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China.
¹⁰ Department of Medical Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
¹¹ Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: bowenke@scu.edu.cn.
¹² Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK. Electronic address: david.kerr@ndcls.ox.ac.uk.
¹³ Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yangli@wchscu.cn.
¹⁴ Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yangjinlin@wchscu.cn.
¹⁵ Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Aging and Cancer, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: haojiang@scu.edu.cn.

PMID: 41406964
DOI: 10.1016/j.cell.2025.11.019

Free article

Targeting TFAP2β condensation suppresses the development of esophageal squamous cell carcinoma

Zhaomin Deng et al. Cell. 2026.

Free article

. 2026 Feb 5;189(3):887-905.e25.

doi: 10.1016/j.cell.2025.11.019. Epub 2025 Dec 16.

Authors

Affiliations

¹ Laboratory of Aging and Cancer, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Medical Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
² Laboratory of Aging and Cancer, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Aging and Cancer, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
³ Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
⁴ Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
⁵ Department of Neurology, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, China.
⁶ Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Cross-Disciplinary Science, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; School of Synthetic Biology and Biomanufacturing, Tianjin University, Tianjin 300072, China.
⁷ Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁸ Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Cross-Disciplinary Science, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
⁹ The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China.
¹⁰ Department of Medical Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
¹¹ Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: bowenke@scu.edu.cn.
¹² Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK. Electronic address: david.kerr@ndcls.ox.ac.uk.
¹³ Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yangli@wchscu.cn.
¹⁴ Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yangjinlin@wchscu.cn.
¹⁵ Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Aging and Cancer, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: haojiang@scu.edu.cn.

PMID: 41406964
DOI: 10.1016/j.cell.2025.11.019

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.

Keywords: TFAP2β; chromatin accessibility; condensation-induced drug; esophageal squamous cell carcinoma; liquid-liquid phase separation; transcription factor.

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Conflict of interest statement

Declaration of interests The optimized ATAC-seq library construction approach and compound A6 have been filed for patent applications.

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Targeting TFAP2β condensation suppresses the development of esophageal squamous cell carcinoma

Affiliations

Targeting TFAP2β condensation suppresses the development of esophageal squamous cell carcinoma

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous