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.

SMARCA4是SWI/SNF染色质重塑复合体的ATP酶亚基，可通过调控染色质可及性在基因调控中发挥核心作用。尽管SMARCA4在肺腺癌（LUAD）中常发生功能失活，但仍有部分肿瘤保留高SMARCA4表达水平，提示其存在依赖于特定细胞背景的致癌功能。然而，SMARCA4在肺腺癌中发挥致癌功能的分子基础仍有待阐明。为解决这一科学问题，本研究探讨了SMARCA4如何调控表观遗传与转录组图谱以促进肿瘤发生。在SMARCA4缺陷的H522肺腺癌细胞系中异位过表达SMARCA4，可显著增强细胞增殖与迁移能力。为解析驱动上述表型变化的分子机制，本研究开展了RNA测序（RNA-seq）与转座酶可及性测序（ATAC-seq）分析，结果显示转录组谱与染色质可及性均发生广泛改变。同时，本研究针对组蛋白修饰H3K4me1与H3K27ac开展了染色质免疫共沉淀测序（ChIP-seq），以表征SMARCA4调控的增强子图谱。整合多组学分析表明，SMARCA4过表达可诱导增强子活化，具体表现为H3K4me1与H3K27ac信号富集程度升高，且与致癌通路相关的基因表达上调。值得注意的是，SMARCA4过表达可促进活性增强子的建立，并显著激活致癌转录程序。对SMARCA4进行药物降解，可降低上述增强子区域的染色质可及性，进而抑制致癌基因表达，并阻断细胞增殖与迁移。与之一致的是，抑制SMARCA4可在异种移植模型中减缓肿瘤生长，进一步证实其在肿瘤发生中的关键作用。从分子机制层面，本研究鉴定出转录因子FOSL1作为关键调控因子，可与SMARCA4及SWI/SNF复合体组分协同促进增强子活化。敲低FOSL1可显著减少SMARCA4、H3K4me1与H3K27ac在增强子区域的结合富集，导致邻近基因表达下调，并损害细胞增殖与迁移能力。上述研究结果明确了SMARCA4与FOSL1之间的表观遗传调控轴，该轴由SMARCA4缺陷的肺腺癌细胞中SMARCA4活化所诱导，为理解SMARCA4在该细胞背景下如何参与致癌调控程序提供了机制层面的深入见解。