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

Qian Tang1,2, Chen Lian1, Xinyan Han1,2

  • 1Department 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.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 26, 2026
PubMed

Insights

SMAD4 loss in lung squamous cell carcinoma (LUSC) disrupts 3D genome organization, activating SOX2 and promoting tumor growth. This reveals a new therapeutic target for LUSC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Lung squamous cell carcinoma (LUSC) lacks defined drivers and targeted therapies.
  • Understanding LUSC molecular pathogenesis is incomplete.

Purpose of the Study:

  • Identify key regulators of LUSC 3D genome organization.
  • Elucidate the link between tumor suppressor loss and oncogenic transcriptional activation in LUSC.

Main Methods:

  • Integrated clinical datasets, genetically engineered mouse models, and LUSC cell lines.
  • Performed multi-omics analyses to study genome organization and gene regulation.
  • Investigated the role of SMAD4 and EP300 in enhancer-promoter looping at the SOX2 locus.

Main Results:

  • SMAD4 deficiency promotes LUSC progression by enabling EP300-mediated enhancer-promoter looping at the SOX2 locus.
  • SMAD4 constrains chromatin looping by sequestering EP300, and its loss leads to aberrant SOX2 activation.
  • SMAD4 loss increases H3K27ac deposition and LUSC tumor cell proliferation.

Conclusions:

  • SMAD4 is a critical regulator of 3D genome organization in LUSC.
  • SMAD4 loss drives LUSC through dysregulated 3D genome architecture and SOX2 activation.
  • Targeting SMAD4 or its downstream effects presents a potential therapeutic strategy for LUSC.
Keywords:
3D genomeSMAD4SOX2lung squamous cell carcinoma

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