Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non-Small Cell Lung Carcinoma.
Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non-Small Cell Lung Carcinoma.
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DOI：
10.1158/1541-7786.mcr-20-0082
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Weissman BE
中科院分区：
文献类型：
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作者：
Song S;Nguyen V;Schrank T;Mulvaney K;Walter V;Wei D;Orvis T;Desai N;Zhang J;Hayes DN;Zheng Y;Major MB;Weissman BE
NF-E2相关因子2（简称NRF2）转录因子与细胞保护基因启动子内的抗氧化反应元件结合，诱导其表达。肺癌的下一代测序研究表明 NRF2 信号通路内存在大量激活突变。 SWI/SNF 染色质重塑复合体（使用 BRG1 或 BRM 作为催化亚基的转录一般调节因子）的成分突变也经常发生在肺癌中。重要的是，原发性人类 NSCLC 中 BRG1 的低表达水平与 NRF2 靶基因表达的增加相关。在这里，我们发现 SWI/SNF 复合体功能的丧失激活了 NRF2 介导的转录靶标的子集。使用一系列 BRG1 和/或 BRM 表达减少或耗尽的同基因 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，BRM 减少后，NRF2 靶基因 NQO1 和 GCLM 的表达略有增加。染色质免疫沉淀显示，BRG1 敲低导致 HMOX1 启动子中各自 ARE 位点的 NRF2 结合增加，但在 NQO1 和 GCLM 中则不然。我们的数据表明，肺癌中 BRG1 或 BRM 的缺失会导致 NRF2/KEAP1 通路和 HMOX1 表达的激活。因此，我们为为什么携带 BRG1 或 BRM 突变的患者表现出不良预后提供了额外的分子解释。更好地理解这一机制可能会对靶向治疗方式的设计产生新的见解。
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 employing 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.