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Hauptverfasser: 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
Format: Artículo Open Access
Veröffentlicht: Wiley 2026
Schlagworte:
Advanced Science
Online-Zugang:https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.75839
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Inhaltsangabe:
  • 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 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. 10.1002/advs.75839 http://creativecommons.org/licenses/by/4.0/

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