NRF2 has a splicing regulatory function involving the survival of motor neuron (SMN) in non-small cell lung cancer
NRF2 has a splicing regulatory function involving the survival of motor neuron (SMN) in non-small cell lung cancer
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DOI：
10.1038/s41388-023-02799-z
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发表时间：
2023-08-12
期刊：
影响因子：
8
通讯作者：
Tang，Xiuwen
中科院分区：
文献类型：
--
作者：
Cui，Qinqin;Wang，Wei;Tang，Xiuwen
核因子类红细胞 2 2 (NFE2L2；NRF2) 信号通路在人类癌症中经常失调。除了转录激活之外，NRF2 在癌症中的关键功能仍然很大程度上未知。在这里，我们发现了 NRF2 在 RNA 剪接调节中以前未被认识的作用。整体剪接分析显示，非小细胞肺癌 (NSCLC) A549 细胞中的 NRF2 敲除改变了 485 个基因中的 839 个选择性剪接 (AS) 事件。机制研究表明，NRF2 通过与 SMN1 启动子中的两个抗氧化反应元件结合来转录调节 SMN mRNA 表达。转录后，NRF2 与 SMN 蛋白物理相关。 NRF2 的 Neh2 结构域以及 YG 盒和 SMN 外显子 7 编码的区域是它们相互作用所必需的。 NRF2与核宝石和卡哈尔小体中的SMN和Gemin2形成复合物。此外，NRF2-SMN相互作用通过在NRF2敲除的HeLa细胞中表达SMN来调节RNA剪接，从而恢复一些改变的RNA剪接。此外，根据癌症基因组图谱，SMN 过度表达与肺鳞状细胞癌患者中 NRF2 通路的改变显着相关。总而言之，我们的研究结果提出了一种针对涉及异常 NRF2 通路的癌症的新治疗策略。
The nuclear factor erythroid 2-like 2 (NFE2L2; NRF2) signaling pathway is frequently deregulated in human cancers. The critical functions of NRF2, other than its transcriptional activation, in cancers remain largely unknown. Here, we uncovered a previously unrecognized role of NRF2 in the regulation of RNA splicing. Global splicing analysis revealed that NRF2 knockdown in non-small cell lung cancer (NSCLC) A549 cells altered 839 alternative splicing (AS) events in 485 genes. Mechanistic studies demonstrated that NRF2 transcriptionally regulated SMN mRNA expression by binding to two antioxidant response elements in theSMN1promoter. Post-transcriptionally, NRF2 was physically associated with the SMN protein. The Neh2 domain of NRF2, as well as the YG box and the region encoded by exon 7 of SMN, were required for their interaction. NRF2 formed a complex with SMN and Gemin2 in nuclear gems and Cajal bodies. Furthermore, the NRF2–SMN interaction regulated RNA splicing by expressing SMN in NRF2-knockout HeLa cells, reverting some of the altered RNA splicing. Moreover, SMN overexpression was significantly associated with alterations in the NRF2 pathway in patients with lung squamous cell carcinoma from The Cancer Genome Atlas. Taken together, our findings suggest a novel therapeutic strategy for cancers involving an aberrant NRF2 pathway.