Department of Systems Pharmacology & Translational Therapeutics, Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Br J Cancer. 2022 May;126(9):1244-1252. doi: 10.1038/s41416-021-01642-0. Epub 2021 Nov 29.
Electrophilic and oxidative stress is caused when homeostatic mechanisms are disrupted. A major defense mechanism involves the activation of the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor encoded by the NFE2L2 gene, which can accelerate the detoxification of electrophilic carcinogens and prevent cancer and on the other hand in certain exposure contexts may exacerbate the carcinogenic process. NRF2-target genes activated under these conditions can be used as biomarkers of stress signalling, while activation of NRF2 can also reveal the epigenetic mechanisms that modulate NFE2L2 expression. Epigenetic mechanisms that regulate NFE2L2 and the gene for its adaptor protein KEAP1 include DNA methylation, histone modifications and microRNA. Understanding the activation of the NRF2-KEAP1 signalling pathway in human lung cancer, its epigenetic regulation and its role in oncogenesis is the subject of this review.
当体内平衡机制被破坏时，就会产生亲电和氧化应激。一种主要的防御机制涉及核因子红细胞 2 相关因子 2 (NRF2) 转录因子的激活，该转录因子由 NFE2L2 基因编码，可加速亲电致癌物质的解毒，预防癌症，而在某些暴露环境下，可能会加剧致癌过程。在这些条件下激活的 NRF2 靶基因可用作应激信号的生物标志物，而 NRF2 的激活也可以揭示调节 NFE2L2 表达的表观遗传机制。调节 NFE2L2 和其衔接蛋白 KEAP1 的基因的表观遗传机制包括 DNA 甲基化、组蛋白修饰和 microRNA。本综述的主题是探讨人类肺癌中 NRF2-KEAP1 信号通路的激活、其表观遗传调控及其在致癌中的作用。
