A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations.
A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations.
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DOI：
10.1016/j.redox.2018.07.026
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发表时间：
2018-10
期刊：
影响因子：
11.4
通讯作者：
Slattery M
中科院分区：
文献类型：
--
作者：
Levings DC;Wang X;Kohlhase D;Bell DA;Slattery M
NRF2是一种氧化还原反应转录因子，通过与称为抗氧化反应元件（战神）的DNA序列相互作用调节细胞保护基因的表达。NRF2活性由氧化应激诱导，但氧化应激不是NRF2可以被激活的唯一环境。破坏NRF2和KEAP 1（NRF2的抑制剂）之间相互作用的突变会导致NRF2过度激活并促进肿瘤发生。NRF2致癌特性的潜在机制仍不清楚，但可能涉及选择NRF2靶基因的异常表达。我们使用整合基因组学方法测试了这种可能性，以精确了解NRF2过度激活突变肿瘤中失调的直接NRF2靶基因。这种方法揭示了一组核心的32个直接NRF2靶点，这些靶点在NRF2过度活化的肿瘤中持续上调。这组NRF2“癌症靶基因”包括典型的氧化还原相关的NRF2靶基因，以及先前未与NRF2激活相关的靶基因。重要的是，NRF2驱动的该基因组的上调在很大程度上独立于肿瘤发生的器官系统。这些NRF2癌症靶基因的一个关键区别特征是，它们受到高亲和力战神的调节，这些ARE位于具有普遍允许的染色质特征的基因组区域内。这意味着这些NRF2癌症靶基因在大多数组织中对致癌NRF2有反应，因为它们缺乏限制大多数其他NRF2靶基因表达的调控约束。该NRF2癌症靶基因集也可作为NRF2活性的可靠替代物，并且高NRF2活性与多种癌症类型的存活率显著降低相关。总体而言，这些NRF2癌症靶点在多种癌症中的普遍上调及其与阴性结果的相关性表明，这些将是剖析NRF2超活化在多种癌症背景下的功能影响的核心。
NRF2 is a redox-responsive transcription factor that regulates expression of cytoprotective genes via its interaction with DNA sequences known as antioxidant response elements (AREs). NRF2 activity is induced by oxidative stress, but oxidative stress is not the only context in which NRF2 can be activated. Mutations that disrupt the interaction between NRF2 and KEAP1, an inhibitor of NRF2, lead to NRF2 hyperactivation and promote oncogenesis. The mechanisms underlying NRF2's oncogenic properties remain unclear, but likely involve aberrant expression of select NRF2 target genes. We tested this possibility using an integrative genomics approach to get a precise view of the direct NRF2 target genes dysregulated in tumors with NRF2 hyperactivating mutations. This approach revealed a core set of 32 direct NRF2 targets that are consistently upregulated in NRF2 hyperactivated tumors. This set of NRF2 “cancer target genes” includes canonical redox-related NRF2 targets, as well as target genes that have not been previously linked to NRF2 activation. Importantly, NRF2-driven upregulation of this gene set is largely independent of the organ system where the tumor developed. One key distinguishing feature of these NRF2 cancer target genes is that they are regulated by high affinity AREs that fall within genomic regions possessing a ubiquitously permissive chromatin signature. This implies that these NRF2 cancer target genes are responsive to oncogenic NRF2 in most tissues because they lack the regulatory constraints that restrict expression of most other NRF2 target genes. This NRF2 cancer target gene set also serves as a reliable proxy for NRF2 activity, and high NRF2 activity is associated with significant decreases in survival in multiple cancer types. Overall, the pervasive upregulation of these NRF2 cancer targets across multiple cancers, and their association with negative outcomes, suggests that these will be central to dissecting the functional implications of NRF2 hyperactivation in several cancer contexts.
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影响因子：
14.9
作者：
Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
通讯作者：
Bell DA
影响因子：
18.4
作者：
Bhagwat AS;Vakoc CR
通讯作者：
Vakoc CR
DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Holtzclaw, WD;Talalay, P
通讯作者：
Talalay, P
影响因子：
64.5
作者：
Chio IIC;Jafarnejad SM;Ponz-Sarvise M;Park Y;Rivera K;Palm W;Wilson J;Sangar V;Hao Y;Öhlund D;Wright K;Filippini D;Lee EJ;Da Silva B;Schoepfer C;Wilkinson JE;Buscaglia JM;DeNicola GM;Tiriac H;Hammell M;Crawford HC;Schmidt EE;Thompson CB;Pappin DJ;Sonenberg N;Tuveson DA
通讯作者：
Tuveson DA
鉴定癌症类型的显着突变区域的鉴定突出了功能分子改变的丰富景观。
影响因子：
30.8
作者：
Araya CL;Cenik C;Reuter JA;Kiss G;Pande VS;Snyder MP;Greenleaf WJ
通讯作者：
Greenleaf WJ