DataVXAdvanced SciencePaper
journal article·2026-05-26Open access

A Non‐Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Qian Tang, Chen Lian, Xinyan Han, Xuhan Zhang, Zihan Wang, Boyu Wang, Taoyu Zhu, Xinrui Lin, Xiaolei Wang, Yaping Xu, Manyu Xiao, Zijin Wang, Junming Li, Silin Chen, Yunze Wang, Yufei Liu, Songsong Li, Zuolin Shen, Xi Lu, Xueqi Han, Yilu Zhou, Mingyang Xiao, Jiayi Ran, Xiaoran Cao, Xinyi Xu, Hugo Sámano‐Sánchez, Alfredo Rodríguez, Lian Wang, Shuifang Chen, Zhanyu Xu, Shirong Zhang, Nuo Yang, Yong Tang, Jian Liu

Advanced Science
Publisher pageOpen full text
Source abstract

Abstract

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.
Source: crossref · Quality: baseline

Research context

Materials processing

OpenAlex topics: Chromatin Remodeling and Cancer · Genomics and Chromatin Dynamics · TGF-β signaling in diseases

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department 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

Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine The University of Edinburgh Edinburgh UK

Zunyi Medical University Zunyi China

Laboratorio De Falla Medular y Carcinogénesis Instituto Nacional de Pediatría Ciudad de México Mexico

Departamento De Medicina Genómica y Toxicología Ambiental, Instituto De Investigaciones Biomédicas, Universidad Nacional Autónoma De México Ciudad Universitaria Ciudad de México Mexico

Department of Thoracic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang University Hangzhou Zhejiang China

First Affiliated Hospital of Zhejiang University Hangzhou Zhejiang China

Department of Respiratory Diseases Haining People's Hospital Haining Zhejiang China

Department of Thoracic Surgery The First Affiliated Hospital of Guangxi Medical University Guangxi China

Department of Molecular Diagnostic Centre, Affiliated Hangzhou First People's Hospital Westlake University School of Medicine Hangzhou Zhejiang China

Department of Thoracic Surgery Shenzhen Nanshan People's Hospital Shenzhen China

Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang China

Zhejiang Key Laboratory of Medical Imaging Artificial Intelligence Haining China

Biomedical and Health Translational Research Center of Zhejiang Province Haining China

Funding

Guangxi Key Research and Development Program

References (49)

Show source-provided references
1. Cancer Statistics, 2025
2. 10.1016/S0140‐6736(22)01694‐410.1016/S0140‐6736(22)01694‐4 ↗
3. 10.1038/s41392‐022‐01200‐x10.1038/s41392‐022‐01200‐x ↗
4. 10.1007/s44178‐025‐00188‐y10.1007/s44178‐025‐00188‐y ↗
5. 10.1007/s44178‐024‐00139‐z10.1007/s44178‐024‐00139‐z ↗
6. 10.1038/s41467‐019‐09843‐110.1038/s41467‐019‐09843‐1 ↗
7. 10.1016/j.ccr.2013.03.00910.1016/j.ccr.2013.03.009 ↗
8. 10.1038/nature0603010.1038/nature06030 ↗
9. 10.1016/j.celrep.2014.05.03610.1016/j.celrep.2014.05.036 ↗
10. 10.1016/j.ccr.2014.03.03310.1016/j.ccr.2014.03.033 ↗
11. 10.1128/JVI.72.7.6014‐6023.199810.1128/JVI.72.7.6014‐6023.1998 ↗
12. 10.1016/j.celrep.2015.02.01410.1016/j.celrep.2015.02.014 ↗
13. 10.1038/s41568‐022‐00488‐910.1038/s41568‐022‐00488‐9 ↗
14. 10.1016/j.gpb.2020.05.00710.1016/j.gpb.2020.05.007 ↗
15. 10.1017/erm.2021.1510.1017/erm.2021.15 ↗
16. 10.1002/advs.20240447610.1002/advs.202404476 ↗
17. 10.1038/nature1140410.1038/nature11404 ↗
18. Dysregulated Tgfbr2/ERK‐Smad4/SOX2 Signaling Promotes Lung Squamous Cell Carcinoma Formation10.1158/0008-5472.CAN-19-0161 ↗
19. 10.1016/j.cell.2017.11.00810.1016/j.cell.2017.11.008 ↗
20. 10.1016/j.stem.2021.04.02310.1016/j.stem.2021.04.023 ↗
21. 10.1101/gad.239749.11410.1101/gad.239749.114 ↗
22. 10.1038/s41467‐021‐24898‐910.1038/s41467‐021‐24898‐9 ↗
23. 10.1038/s41580‐024‐00710‐610.1038/s41580‐024‐00710‐6 ↗
24. 10.1038/s41580‐018‐0028‐810.1038/s41580‐018‐0028‐8 ↗
25. 10.1038/ng.46510.1038/ng.465 ↗
26. 10.1038/s41598‐018‐20086‐w10.1038/s41598‐018‐20086‐w ↗
27. 10.1016/j.semcancer.2020.05.00710.1016/j.semcancer.2020.05.007 ↗
28. 10.1016/j.canlet.2006.01.00310.1016/j.canlet.2006.01.003 ↗
29. 10.1002/cncr.1072710.1002/cncr.10727 ↗
30. 10.1016/j.cell.2017.10.04410.1016/j.cell.2017.10.044 ↗
31. 10.1038/s41392‐022‐00946‐810.1038/s41392‐022‐00946‐8 ↗
32. 10.1101/gad.12.14.211410.1101/gad.12.14.2114 ↗
33. 10.1016/j.lungcan.2017.08.00110.1016/j.lungcan.2017.08.001 ↗
34. 10.1038/s41419‐020‐02820‐310.1038/s41419‐020‐02820‐3 ↗
35. 10.1111/j.1440‐1681.2006.04403.x10.1111/j.1440‐1681.2006.04403.x ↗
36. From FastQ Data to High‐Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline10.1002/0471250953.bi1110s43 ↗
37. F.Krueger F.James P.Ewels E.Afyounian M.Weinstein et al. FelixKrueger/TrimGalore: v0.6.10 – add Default Decompression Path(2023).
38. 10.1038/s41587‐019‐0201‐410.1038/s41587‐019‐0201‐4 ↗
39. Broad Institute Broad Institute GitHub Repository(2019).
40. Twelve Years of SAMtools and BCFtools10.1093/gigascience/giab008 ↗
41. 10.1093/bioinformatics/btt65610.1093/bioinformatics/btt656 ↗
42. 10.1038/s41596‐024‐01020‐z10.1038/s41596‐024‐01020‐z ↗
43. 10.1038/nmeth.192310.1038/nmeth.1923 ↗
44. 10.1093/nar/gkw25710.1093/nar/gkw257 ↗
45. 10.1093/bib/bbs01710.1093/bib/bbs017 ↗
46. 10.1186/gb‐2008‐9‐9‐r13710.1186/gb‐2008‐9‐9‐r137 ↗
47. 10.1186/s13059‐015‐0831‐x10.1186/s13059‐015‐0831‐x ↗
48. 10.1016/j.cels.2015.07.01210.1016/j.cels.2015.07.012 ↗
49. 10.1093/nar/gkaa22010.1093/nar/gkaa220 ↗