The NF-E2–related factor 2 (referred to as NRF2) transcription factor binds antioxidant responsive elements within the promoters of cytoprotective genes to induce their expression. Next-generation sequencing studies in lung cancer have shown a significant number of activating mutations within the NRF2 signaling pathway. Mutations in components of the SWI/SNF chromatin-remodeling complex, a general regulator of transcription using either BRG1 or BRM as the catalytic subunit, also frequently occur in lung cancers. Importantly, low BRG1 expression levels in primary human NSCLC correlated with increased NRF2-target gene expression. Here, we show that loss of SWI/SNF complex function activated a subset of NRF2-mediated transcriptional targets. Using a series of isogenic NSCLC lines with reduced or depleted BRG1 and/or BRM expression, we observed significantly increased expression of the NRF2-target genes HMOX1 and GSTM4. In contrast, expression of the NRF2 target genes NQO1 and GCLM modestly increased following BRM reduction. Chromatin immunoprecipitation showed that BRG1 knockdown led to increased NRF2 binding at its respective ARE sites in the HMOX1 promoter but not in NQO1 and GCLM. Our data demonstrate that loss of BRG1 or BRM in lung cancer results in activation of the NRF2/KEAP1 pathway and HMOX1 expression. Therefore, we provide an additional molecular explanation for why patients harboring BRG1 or BRM mutations show poor prognoses. A better understanding of this mechanism may yield novel insights into the design of targeted treatment modalities. Implications: Our study identifies a novel mechanism for how mutations in the SMARCA4 gene may drive progression of human lung adenocarcinomas.

中文翻译：

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SWI/SNF染色质重塑的缺失改变了非小细胞肺癌中的NRF2信号传导

NF-E2 相关因子 2（称为 NRF2）转录因子结合细胞保护基因启动子内的抗氧化反应元件以诱导其表达。肺癌的新一代测序研究显示 NRF2 信号通路中存在大量激活突变。SWI/SNF 染色质重塑复合物（一种使用 BRG1 或 BRM 作为催化亚基的转录的一般调节剂）成分的突变也经常发生在肺癌中。重要的是，原发性人类 NSCLC 中的低 BRG1 表达水平与 NRF2 靶基因表达增加相关。在这里，我们表明 SWI/SNF 复合功能的丧失激活了 NRF2 介导的转录目标的一个子集。使用一系列具有降低或耗尽 BRG1 和/或 BRM 表达的同基因 NSCLC 系，我们观察到 NRF2 靶基因 HMOX1 和 GSTM4 的表达显着增加。相比之下，NRF2 靶基因 NQO1 和 GCLM 的表达在 BRM 减少后适度增加。染色质免疫沉淀显示 BRG1 敲低导致 NRF2 在 HMOX1 启动子中其各自 ARE 位点的结合增加，但在 NQO1 和 GCLM 中没有。我们的数据表明，肺癌中 BRG1 或 BRM 的缺失导致 NRF2/KEAP1 通路和 HMOX1 表达的激活。因此，我们为携带 BRG1 或 BRM 突变的患者预后不佳的原因提供了额外的分子解释。更好地理解这种机制可能会对靶向治疗方式的设计产生新的见解。含义：