Luo George, Kumar Harshita, Aldridge Kristin, Rieger Stevie, Han EunHyang, Jiang Ethan, Chan Ernest R, Soliman Ahmed, Mahdi Haider, Letterio John J
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Department of Engineering, Case Western Reserve University, Cleveland, Ohio, USA.
Antioxid Redox Signal. 2024 Dec;41(16-18):1031-1050. doi: 10.1089/ars.2023.0409. Epub 2024 Aug 8.
The nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (NRF2-KEAP1) pathway plays an important role in the cellular response to oxidative stress but may also contribute to metabolic changes and drug resistance in cancer. However, despite its pervasiveness and important role, most of nuclear factor erythroid 2-related factor 2 (NRF2) target genes are defined in context-specific experiments and analysis, making it difficult to translate from one situation to another. Our study investigates whether a core NRF2 gene signature can be derived and used to represent NRF2 activation in various contexts, allowing better reproducibility and understanding of NRF2. We define a core set of 14 upregulated NRF2 target genes from 7 RNA-sequencing datasets that we generated and analyzed. This NRF2 gene signature was validated using analyses of published datasets and gene sets. An NRF2 activity score based on expression of these core target genes correlates with resistance to drugs such as PX-12 and necrosulfonamide but not to paclitaxel or bardoxolone methyl. We validated these findings in our Kelch-like ECH-associated protein 1 () knockout cancer cell lines. Finally, our NRF2 score is prognostic for cancer survival and validated in additional independent cohorts for lung adenocarcinoma and also novel cancer types not associated with NRF2-KEAP1 mutations such as clear cell renal carcinoma, hepatocellular carcinoma, and acute myeloid leukemia. These analyses define a core NRF2 gene signature that is robust, versatile, and useful for evaluating NRF2 activity and for predicting drug resistance and cancer prognosis. Using this gene signature, we uncovered novel selective drug resistance and cancer prognosis associated with NRF2 activation. 41, 1031-1050.
核因子红细胞2相关因子2- Kelch样ECH相关蛋白1（NRF2-KEAP1）通路在细胞对氧化应激的反应中起重要作用，但也可能导致癌症中的代谢变化和耐药性。然而，尽管其普遍存在且作用重要，但大多数核因子红细胞2相关因子2（NRF2）靶基因是在特定背景的实验和分析中确定的，这使得难以从一种情况转换到另一种情况。我们的研究调查是否可以推导并使用一个核心NRF2基因特征来代表各种背景下的NRF2激活，从而实现更好的可重复性并增进对NRF2的理解。我们从我们生成并分析的7个RNA测序数据集中定义了一组由14个上调的NRF2靶基因组成的核心基因集。使用已发表的数据集和基因集分析对该NRF2基因特征进行了验证。基于这些核心靶基因表达的NRF2活性评分与对PX-12和坏死磺酰胺等药物的耐药性相关，但与紫杉醇或巴多昔隆甲基无关。我们在我们的Kelch样ECH相关蛋白1（）敲除癌细胞系中验证了这些发现。最后，我们的NRF2评分对癌症生存具有预后价值，并在另外的独立队列中针对肺腺癌以及与NRF2-KEAP1突变无关的新型癌症类型（如透明细胞肾细胞癌、肝细胞癌和急性髓细胞白血病）得到了验证。这些分析定义了一个核心NRF2基因特征，该特征强大、通用且可用于评估NRF2活性以及预测耐药性和癌症预后。使用这个基因特征，我们发现了与NRF2激活相关的新型选择性耐药性和癌症预后。41, 1031 - 1050。
