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<p>SMARCA4, the ATPase component of the SWI/SNF chromatin remodeling complex, is integral to the regulation of gene expression through modulation of chromatin accessibility. Although SMARCA4 is frequently inactivated in lung adenocarcinoma (LUAD), a subset of tumors exhibits elevated SMARCA4 expression, suggesting a context-dependent oncogenic function. However, the molecular mechanisms by which elevated SMARCA4 exerts oncogenic functions in LUAD remain unclear. Here, using a SMARCA4-deficient LUAD cellular model, we show that SMARCA4 overexpression reorganizes enhancer landscapes and establishes a cooperative transcriptional network involving FOSL1, thereby promoting cancer cell proliferation and tumorigenic phenotypes. Integrative multi-omics analyses revealed that SMARCA4 directly cooperates with FOSL1 at active enhancers, leading to the activation of tumor-associated transcriptional programs. Functionally, genetic depletion of FOSL1 or pharmacological inhibition of SMARCA4 reduced cell proliferation and migration and suppressed tumor growth in vitro and in vivo. Importantly, high co-expression of SMARCA4 and FOSL1 was associated with poor clinical outcomes in LUAD patient cohorts. Together, these findings define an epigenetic regulatory axis between SMARCA4 and FOSL1 induced by SMARCA4 activation in SMARCA4-deficient LUAD cells, thereby providing mechanistic insight into how SMARCA4 activates oncogenic regulatory programs in this specific cellular context.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Hye-Ju Yang,
  • Eun-Ju Kim,
  • Sungho Kim,
  • Sang-Hyun Song,
  • Tae-You Kim

摘要

SMARCA4, the ATPase component of the SWI/SNF chromatin remodeling complex, is integral to the regulation of gene expression through modulation of chromatin accessibility. Although SMARCA4 is frequently inactivated in lung adenocarcinoma (LUAD), a subset of tumors exhibits elevated SMARCA4 expression, suggesting a context-dependent oncogenic function. However, the molecular mechanisms by which elevated SMARCA4 exerts oncogenic functions in LUAD remain unclear. Here, using a SMARCA4-deficient LUAD cellular model, we show that SMARCA4 overexpression reorganizes enhancer landscapes and establishes a cooperative transcriptional network involving FOSL1, thereby promoting cancer cell proliferation and tumorigenic phenotypes. Integrative multi-omics analyses revealed that SMARCA4 directly cooperates with FOSL1 at active enhancers, leading to the activation of tumor-associated transcriptional programs. Functionally, genetic depletion of FOSL1 or pharmacological inhibition of SMARCA4 reduced cell proliferation and migration and suppressed tumor growth in vitro and in vivo. Importantly, high co-expression of SMARCA4 and FOSL1 was associated with poor clinical outcomes in LUAD patient cohorts. Together, these findings define an epigenetic regulatory axis between SMARCA4 and FOSL1 induced by SMARCA4 activation in SMARCA4-deficient LUAD cells, thereby providing mechanistic insight into how SMARCA4 activates oncogenic regulatory programs in this specific cellular context.