ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026
A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development.
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Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Carmn sustains basal stemness in exocrine glands and CTND1-mediated Wnt signaling in mammary tissue.EMBO reports · 2026Article
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34 authors.
Qian TangDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Chen LianDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Xinyan HanDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Xuhan ZhangDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Zihan WangDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Boyu WangDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Taoyu ZhuDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Xinrui LinDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Xiaolei WangDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Yaping XuDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Manyu XiaoDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Zijin WangDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Junming LiDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Silin ChenDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Yunze WangDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Yufei LiuDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Songsong LiDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Zuolin ShenDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Xi LuDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Xueqi HanDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Yilu ZhouDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Mingyang XiaoDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Jiayi RanDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Xiaoran CaoDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Xinyi XuDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Hugo Sámano-SánchezDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Alfredo RodríguezLaboratorio De Falla Medular y Carcinogénesis, Instituto Nacional de Pediatría, Ciudad de México, Mexico.
Lian WangDepartment of Thoracic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Shuifang ChenFirst Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China.
Zhanyu XuDepartment of Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Shirong ZhangDepartment of Molecular Diagnostic Centre, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China.
Nuo YangDepartment of Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China.ORCID https://orcid.org/0009-0006-4623-8913
Yong TangDepartment of Thoracic Surgery, Shenzhen Nanshan People's Hospital, Shenzhen, China.
Jian LiuDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China.
Funding
Cross Lung Research AllianceDr. Li Dak Sum & Yip Yio Chin Development Fund for Regenerative Medicine, Zhejiang UniversityFoundation from the Health Bureau of Zhejiang Province 2022KY804Guangxi Key Research and Development Program GuiKe-AB25069017Haining People's Hospital Tertiary-A Public Hospital Establishment Project Municipal Finance Support FundJoint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation 2024GXNSFAA010101Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation 2024GXNSFBA010032Joint University-Local Cooperation Fund between ZJU-UoE Institute and Haining People's HospitalNatural Science Foundation (NSF) of China 82172899Natural Science Foundation (NSF) of China 82472637Noncommunicable Chronic Diseases-National Science and Technology Major Project 2023ZD0502900/2023ZD0502902Noncommunicable Chronic Diseases-National Science and Technology Major Project 2023ZD0507500/2023ZD0507501NSF of Zhejiang Province LRG26H160001Sanming Project of Medicine in Shenzhen SZSM202403006Xinmiao Project of Zhejiang Provincial Applied Basic Research Program 2026XMZD031Zhejiang Province Pioneer Research and Development Project 2025C02091ZJE 2024 International Campus Talent Special Funding ProgramZJE Career Development Programme of ZJU international campus-lung and multi-organ research hubZJE Seed FundingZJE-UoE Joint Research Project, Startup Funding of Tenure-track Assistant Professor of Zhejiang University
Abstract
Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.
Indexed as
Carcinoma, Squamous CellLung NeoplasmsSmad4 ProteinAnimalsCell Line, TumorGene Expression Regulation, NeoplasticHumansMiceSOXB1 Transcription FactorsSmad4 ProteinSMAD4 protein, humanSmad4 protein, mouseSOXB1 Transcription Factors3D genomelung squamous cell carcinomaSMAD4SOX2
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.