CEBPB is required for NRF2-mediated drug resistance in NRF2-activated non-small cell lung cancer cells
CEBPB is required for NRF2-mediated drug resistance in NRF2-activated non-small cell lung cancer cells
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DOI：
10.1093/jb/mvac013
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发表时间：
2022-02-07
影响因子：
2.7
通讯作者：
Motohashi，Hozumi
中科院分区：
文献类型：
--
作者：
Okazaki，Keito;Anzawa，Hayato;Motohashi，Hozumi
NRF 2是一种转录激活因子，在抗氧化应激的细胞保护中起关键作用。虽然NRF 2活性的增加主要对我们的健康有益，但癌细胞中的NRF 2活化是有害的，因为它会推动癌细胞的恶性进展。我们先前发现CCAAT/增强子结合蛋白B（CEBPB）在NRF 2激活的肺癌中与NRF 2协同作用，并通过促进NOTCH 3表达增强肿瘤起始活性。然而，CEBPB在肺癌中的一般贡献是相当有争议的，可能是因为CEBPB的作用取决于每个细胞环境中的协作转录因子。为了了解NRF 2如何在NRF 2激活的肺癌中塑造CEBPB的功能及其生物学后果，我们全面探索了NRF 2-CEBPB共调节基因，发现参与药物代谢和解毒的基因特征性富集。事实上，CEBPB和NRF 2协同促进耐药性。我们还发现CEBPB受NRF 2的直接调控，这可能有利于NRF 2和CEBPB的共表达和协同功能。这些结果表明，NRF 2激活的肺癌耐药是通过NRF 2和CEBPB的协同作用实现的。
NRF2 is a transcription activator that plays a key role in cytoprotection against oxidative stress. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental, as it drives their malignant progression. We previously found that CCAAT/enhancer-binding protein B (CEBPB) cooperates with NRF2 in NRF2-activated lung cancer and enhances tumour-initiating activity by promotingNOTCH3expression. However, the general contribution of CEBPB in lung cancer is rather controversial, probably because the role of CEBPB depends on cooperating transcription factors in each cellular context. To understand how NRF2 shapes the function of CEBPB in NRF2-activated lung cancers and its biological consequence, we comprehensively explored NRF2-CEBPB–coregulated genes and found that genes involved in drug metabolism and detoxification were characteristically enriched. Indeed, CEBPB and NRF2 cooperatively contribute to the drug resistance. We also found that CEBPB is directly regulated by NRF2, which is likely to be advantageous for the coexpression and cooperative function of NRF2 and CEBPB. These results suggest that drug resistance of NRF2-activated lung cancers is achieved by the cooperative function of NRF2 and CEBPB.