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

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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Publication Details

Journal
Oncogene
Published
2026-09-18
DOI
https://doi.org/10.1038/s41388-026-03984-6
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
0.00
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article

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

Zhanyu Xu, Manyu Xiao, Zijin Wang, Boyu Wang et al.
Oncogene
Genomics and Chromatin Dynamics
article

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

Zhanyu Xu, Manyu Xiao, Zijin Wang, Boyu Wang, You Yu, Xueqi Han, Martin Košař, Yong Tang, Yao Yao, Lian Chen, Jian Liu, Junming Li, Lian Wang, Songsong Li, Shirong Zhang, Ying Chi, Xi Lu, Chun-Shu Yu, Nuo Yang, Yaping Xu, Silin Chen, Yijiang Guo, Bo Yang, Shuifang Chen, Yilu Zhou, Zuolin Shen, Xiaoke Chen, Junqiang Fan, Huiran Wang, Ran Ji, Yunze Wang, Yufei Liu, Jiaqi Deng, Xinyan Han, Zhenting Zhang
article en

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.

Oncogene
Edinburgh College (GB), Westlake University (CN), Institute for Stem Cell Biology and Regenerative Medicine (IN), ShenZhen People’s Hospital (CN), First Affiliated Hospital of GuangXi Medical University (CN), First People's Hospital of Nanning (CN), Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN), Second Affiliated Hospital of Zhejiang University (CN), Zhejiang University-University of Edinburgh Institute (CN), Artificial Intelligence in Medicine (Canada) (CA), First Affiliated Hospital Zhejiang University (CN), University of Edinburgh (GB)
Openalex Percentile: Top 18%
Genomics and Chromatin Dynamics
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