SMARCA4 reprograms enhancers and activates oncogenic transcriptional programs in cooperation with the key transcription facotr FOSL1, thereby promoting increased cell proliferation, migration, and tumorigenesis.
SMARCA4, the ATPase subunit of the SWI/SNF chromatin remodeling complex, plays a pivotal role in gene regulation by modulating chromatin accessibility. Although SMARCA4 is frequently inactivated in lung adenocarcinoma (LUAD), a subset of tumors retains high SMARCA4 expression, suggesting a potential context-dependent oncogenic role. However, the molecular basis underlying this oncogenic function of SMARCA4 in LUAD remains poorly understood. To address this, we investigated how SMARCA4 influences the epigenetic and transcriptional landscape to promote tumorigenesis. Ectopic overexpression of SMARCA4 in the SMARCA4-deficient H522 LUAD cell line markedly enhanced cell proliferation and migration. To elucidate the molecular mechanisms driving these phenotypic changes, we performed RNA-seq and ATAC-seq analyses, which revealed widespread alterations in transcriptomic profiles and chromatin accessibility. In parallel, ChIP-seq for histone modifications H3K4me1 and H3K27ac was conducted to characterize the enhancer landscape regulated by SMARCA4. Integrated multi-omics analyses demonstrated that SMARCA4 overexpression leads to enhancer activation, marked by gains in H3K4me1 and H3K27ac, and upregulation of genes associated with oncogenic pathways. Notably, SMARCA4 overexpression facilitated the establishment of active enhancers and robust activation of oncogenic transcriptional programs. Pharmacological degradation of SMARCA4 resulted in reduced chromatin accessibility at these enhancers, leading to suppression of oncogenic gene expression and inhibition of cell proliferation and migration. Consistently, SMARCA4 inhibition attenuated tumor growth in xenograft models, highlighting its role in tumorigenesis. Mechanistically, we identified FOSL1 as a key transcription factor that cooperates with SMARCA4 and SWI/SNF complex components to promote enhancer activation. Depletion of FOSL1 significantly diminished SMARCA4, H3K4me1, and H3K27ac occupancy at enhancers, leading to the downregulation of adjacent gene expression and impaired cellular proliferation and migration. These findings define an epigenetic regulatory axis between SMARCA4 and FOSL1, induced by SMARCA4 activation in SMARCA4-deficient LUAD cells, providing mechanistic insight into how SMARCA4 engages oncogenic regulatory programs in this cellular context.