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Peer-reviewedCC BY-NC-ND 4.0Oncogene

A canonical role of SMAD4 in safeguarding 3D genome architecture to suppress lung tumorigenesis

  • Yaping Xu1,2,3
  • Xinyan Han1,2,3
  • Junming Li1,2,3
  • Shirong Zhang4
  • Chen Lian1,3
  • Chenghang Yu1,2
  • Zhanyu Xu5
  • Zhenting Zhang1,2
  • Bo Yang1,2
  • Ran Ji1,2
  • Huiran Wang1,2
  • Manyu Xiao1,3
23 more authors
  • Zijin Wang1,3
  • Boyu Wang1,3
  • Silin Chen1,3
  • Yunze Wang1,2,3
  • Yufei Liu1,2,3
  • Songsong Li1,3
  • Zuolin Shen1,2,3
  • Xi Lu1,3
  • Xueqi Han1,3
  • Yilu Zhou1,3
  • Yao Yao1,2,3
  • Jiaqi Deng1,2,3
  • Yijiang Guo1,2
  • Lian Wang6
  • Shuifang Chen7,8
  • Xiaoke Chen6
  • Ying Chi2,3,9
  • You Yu2,3,9,10
  • Yong Tang11
  • Martin Kosar2,9,12
  • Junqiang Fan6
  • Nuo Yang5
  • Jian Liu1,2,3,13,14,15
15 affiliations
  1. 1Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
  2. 2Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK
  3. 3ZJE Cross Lung Research Alliance, International Joint Center for Biomedical Sciences (Haining), Zhejiang University, Haining, China
  4. 4Department of Molecular Diagnostic Centre, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China
  5. 5Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Guangxi, China
  6. 6Department of Thoracic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
  7. 7First Affiliated Hospital of Zhejiang University, Hangzhou, China
  8. 8Department of Respiratory Diseases, Haining People’s Hospital, Haining, China
  9. 9Department of Pharmacy of the Second Affiliated Hospital of Zhejiang University School of Medicine, and ZJE, Zhejiang University, Hangzhou, China
  10. 10Department of Cardiology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
  11. 11Department of Thoracic Surgery, Shenzhen Nanshan People’s Hospital, Shenzhen, China
  12. 12Department of Burns, the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
  13. 13Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, China
  14. 14Zhejiang Key Laboratory of Medical Imaging Artificial Intelligence, Haining, China
  15. 15Biomedical and Health Translational Research Center of Zhejiang Province, Haining, China
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Abstract

Dysregulation of three-dimensional (3D) genome architecture is a hallmark of cancer, yet the mechanisms by which its disruption drives tumorigenesis remain incompletely understood. Here, we demonstrated that SMAD4 regulated 3D genome organization through its canonical transcription factor activity by directly binding chromatin, thereby suppressing lung tumorigenesis. Hi-C analyses of human lung tumors identify SMAD4 as a potential regulator of 3D genome integrity. Using PTEN-deficient human bronchial epithelial cells and genetically engineered mouse models, we showed that SMAD4 loss induced widespread reorganization of chromatin compartments, topologically associating domain (TAD) boundaries, and chromatin loops, leading to oncogenic transcriptional rewiring during early tumorigenesis. Mechanistically, SMAD4 directly bound chromatin loops and spatially connected gene promoters with active or repressive regulatory elements to control transcription. Upon SMAD4 ablation, enhancer–promoter rewiring dysregulated critical oncogenic drivers, including ELF3. Functional manipulation of an SMAD4-regulated ELF3-associated chromatin loop altered ELF3 expression and cell survival both in vitro and in vivo. Collectively, our findings establish SMAD4 as a direct regulator of 3D genome architecture through classical transcription factor binding to chromatin loops and reveal enhancer–promoter rewiring as a key mechanism driving lung tumorigenesis and a potential therapeutic vulnerability in SMAD4-deficient lung cancer.

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Cite

BibTeXRIS
BibTeX
@article{xu2026canonical,
  title = {{A canonical role of SMAD4 in safeguarding 3D genome architecture to suppress lung tumorigenesis}},
  author = {Yaping Xu and Xinyan Han and Junming Li and Shirong Zhang and Chen Lian and Chenghang Yu and Zhanyu Xu and Zhenting Zhang and Bo Yang and Ran Ji and Huiran Wang and Manyu Xiao and Zijin Wang and Boyu Wang and Silin Chen and Yunze Wang and Yufei Liu and Songsong Li and Zuolin Shen and Xi Lu and Xueqi Han and Yilu Zhou and Yao Yao and Jiaqi Deng and Yijiang Guo and Lian Wang and Shuifang Chen and Xiaoke Chen and Ying Chi and You Yu and Yong Tang and Martin Kosar and Junqiang Fan and Nuo Yang and Jian Liu},
  journal = {Oncogene},
  year = {2026},
  month = sep,
  doi = {10.1038/s41388-026-03984-6},
  url = {https://doi.org/10.1038/s41388-026-03984-6},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - A canonical role of SMAD4 in safeguarding 3D genome architecture to suppress lung tumorigenesis
AU  - Yaping Xu
AU  - Xinyan Han
AU  - Junming Li
AU  - Shirong Zhang
AU  - Chen Lian
AU  - Chenghang Yu
AU  - Zhanyu Xu
AU  - Zhenting Zhang
AU  - Bo Yang
AU  - Ran Ji
AU  - Huiran Wang
AU  - Manyu Xiao
AU  - Zijin Wang
AU  - Boyu Wang
AU  - Silin Chen
AU  - Yunze Wang
AU  - Yufei Liu
AU  - Songsong Li
AU  - Zuolin Shen
AU  - Xi Lu
AU  - Xueqi Han
AU  - Yilu Zhou
AU  - Yao Yao
AU  - Jiaqi Deng
AU  - Yijiang Guo
AU  - Lian Wang
AU  - Shuifang Chen
AU  - Xiaoke Chen
AU  - Ying Chi
AU  - You Yu
AU  - Yong Tang
AU  - Martin Kosar
AU  - Junqiang Fan
AU  - Nuo Yang
AU  - Jian Liu
PY  - 2026
DA  - 2026/09/18
JO  - Oncogene
DO  - 10.1038/s41388-026-03984-6
UR  - https://doi.org/10.1038/s41388-026-03984-6
AB  - Dysregulation of three-dimensional (3D) genome architecture is a hallmark of cancer, yet the mechanisms by which its disruption drives tumorigenesis remain incompletely understood. Here, we demonstrated that SMAD4 regulated 3D genome organization through its canonical transcription factor activity by directly binding chromatin, thereby suppressing lung tumorigenesis. Hi-C analyses of human lung tumors identify SMAD4 as a potential regulator of 3D genome integrity. Using PTEN-deficient human bronchial epithelial cells and genetically engineered mouse models, we showed that SMAD4 loss induced widespread reorganization of chromatin compartments, topologically associating domain (TAD) boundaries, and chromatin loops, leading to oncogenic transcriptional rewiring during early tumorigenesis. Mechanistically, SMAD4 directly bound chromatin loops and spatially connected gene promoters with active or repressive regulatory elements to control transcription. Upon SMAD4 ablation, enhancer–promoter rewiring dysregulated critical oncogenic drivers, including ELF3. Functional manipulation of an SMAD4-regulated ELF3-associated chromatin loop altered ELF3 expression and cell survival both in vitro and in vivo. Collectively, our findings establish SMAD4 as a direct regulator of 3D genome architecture through classical transcription factor binding to chromatin loops and reveal enhancer–promoter rewiring as a key mechanism driving lung tumorigenesis and a potential therapeutic vulnerability in SMAD4-deficient lung cancer.
SN  - 0950-9232
SN  - 1476-5594
ER  -