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Updated: Apr 22, 2026

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SMARCA4 activation engages FOSL1 to drive enhancer reprogramming and tumorigenic phenotypes in SMARCA4-deficient LUAD

Hye-Ju Yang1,2, Eun-Ju Kim1,2, Sungho Kim3

  • 1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.

Cell Death Discovery
|April 20, 2026
PubMed

Insights

Elevated SMARCA4 expression in lung adenocarcinoma (LUAD) promotes cancer by reorganizing enhancers and cooperating with FOSL1. Inhibiting this axis reduces tumor growth, offering new therapeutic targets for LUAD patients.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Molecular Oncology

Background:

  • SMARCA4 (SWI/SNF complex ATPase) regulates gene expression and chromatin accessibility.
  • While often inactivated, SMARCA4 overexpression in lung adenocarcinoma (LUAD) suggests context-specific oncogenic roles.
  • Mechanisms of SMARCA4's oncogenic function in LUAD remain largely unknown.

Purpose of the Study:

  • Investigate the molecular mechanisms of oncogenic SMARCA4 overexpression in LUAD.
  • Elucidate the role of SMARCA4 in regulating gene expression and chromatin landscapes in LUAD.
  • Identify potential therapeutic targets based on SMARCA4's function in LUAD.

Main Methods:

  • Utilized a SMARCA4-deficient LUAD cellular model.
  • Performed integrative multi-omics analyses (genomics, epigenomics, transcriptomics).
  • Conducted genetic depletion and pharmacological inhibition experiments.

Main Results:

  • SMARCA4 overexpression reshapes enhancer landscapes and creates a transcriptional network with FOSL1.
  • SMARCA4 and FOSL1 cooperate at active enhancers, activating tumor-promoting genes.
  • Inhibition of SMARCA4 or FOSL1 suppressed LUAD cell proliferation, migration, and tumor growth.
  • High SMARCA4/FOSL1 co-expression correlates with poor clinical outcomes in LUAD patients.

Conclusions:

  • SMARCA4 activation in SMARCA4-deficient LUAD cells establishes an epigenetic axis with FOSL1.
  • This SMARCA4-FOSL1 axis drives oncogenic regulatory programs and tumor progression.
  • Targeting the SMARCA4-FOSL1 interaction presents a potential therapeutic strategy for LUAD.

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