Department of Biochemistry and Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, P. R. China.
Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, P. R. China.
Oncogene. 2023 Sep;42(37):2751-2763. doi: 10.1038/s41388-023-02799-z. Epub 2023 Aug 12.
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 the SMN1 promoter. 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.
核因子红细胞 2 样 2（NFE2L2；NRF2）信号通路在人类癌症中经常失调。NRF2 的关键功能，除了其转录激活，在癌症中仍然很大程度上未知。在这里，我们揭示了 NRF2 在 RNA 剪接调控中的一个以前未被认识的作用。全局剪接分析显示，NRF2 在非小细胞肺癌（NSCLC）A549 细胞中的敲低改变了 485 个基因中的 839 个可变剪接（AS）事件。机制研究表明，NRF2 通过结合 SMN1 启动子中的两个抗氧化反应元件，转录调控 SMN mRNA 的表达。在转录后水平，NRF2 与 SMN 蛋白在物理上相互作用。NRF2 的 Neh2 结构域，以及 SMN 的 YG 盒和 7 号外显子编码的区域，是它们相互作用所必需的。NRF2 与 SMN 和 Gemin2 在核小体和 Cajal 体中形成复合物。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，逆转了一些改变的 RNA 剪接。此外，SMN 的过表达与癌症患者中 NRF2 通路的改变显著相关，这些患者来自癌症基因组图谱。总之，我们的研究结果表明，针对涉及异常 NRF2 通路的癌症，存在一种新的治疗策略。
