Abstract 4108: SMARCA4-driven oncogenic enhancer and transcriptional reprogramming in non-small cell lung cancer

Abstract SMARCA4, an ATPase subunit of the SWI/SNF complex, is frequently mutated in cancers and plays a crucial role in chromatin remodeling and gene regulation. However, the mechanisms by which SMARCA4 drives oncogenesis in non-small cell lung cancer (NSCLC) remain poorly understood. In this study, we show that SMARCA4 restoration in SMARCA4-deficient NSCLC cells significantly enhances cell proliferation and migration. ATAC-seq and ChIP-seq analyses revealed that SMARCA4 restoration induces extensive epigenetic reprogramming, including altered chromatin accessibility, histone modifications, and activation of enhancers near genes linked to proliferation and migration. These changes were accompanied by increased expression of these genes, suggesting that SMARCA4-mediated enhancer reprogramming promotes oncogenic pathways. Motif analysis identified FOSL1 as a key transcription factor that collaborates with SMARCA4 by physically interacting with SWI/SNF subunits to activate enhancers. Enhanced FOSL1 binding correlated with the upregulation of proliferation- and migration-associated genes. Notably, FOSL1 knockout reduced the expression of these genes and suppressed cell growth, highlighting its critical role in SMARCA4-driven tumorigenesis. Furthermore, targeting SMARCA4 with small molecules such as BRM014 and ACBI1 selectively impaired cell viability in SMARCA4-restored cells, underscoring their potential as therapeutic agents for SMARCA4-dependent cancers. These findings reveal a central role for SMARCA4 in epigenetic regulation and enhancer activation, driven by the SMARCA4/FOSL1 axis, and offer insights into potential therapeutic strategies for NSCLC. Citation Format: Hye-Ju Yang, Eun-Ju Kim, Sang-Hyeon Song, Tae-You Kim. SMARCA4-driven oncogenic enhancer and transcriptional reprogramming in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4108.