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A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations.

ABSTRACT: 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.

SUBMITTER: Levings DC

PROVIDER: S-EPMC6128101 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations.

Levings Daniel C DC Wang Xuting X Kohlhase Derek D Bell Douglas A DA Slattery Matthew M

Redox biology 20180822

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 ...[more]

PMID: 30195190

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Project description:Activation of the Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and consequent induction of phase 2 antioxidant enzymes is known to afford neuroprotection. Here, we present a series of novel electrophilic compounds that protect neurons via this pathway. Natural products, such as carnosic acid (CA), are present in high amounts in the herbs rosemary and sage as ortho-dihydroquinones, and have attracted particular attention because they are converted by oxidative stress to their active form (ortho-quinone species) that stimulate the Keap1/Nrf2 transcriptional pathway. Once activated, this pathway leads to the production of a series of antioxidant phase 2 enzymes. Thus, such dihydroquinones function as redox-activated 'pro-electrophiles'. Here, we explored the concept that related para-dihydroquinones represent even more effective bioactive pro-electrophiles for the induction of phase 2 enzymes without producing toxic side effects. We synthesized several novel para-hydroquinone-type pro-electrophilic compounds (designated D1 and D2) to analyze their protective mechanism. DNA microarray, PCR, and western blot analyses showed that compound D1 induced expression of heat-shock proteins (HSPs), including HSP70, HSP27, and DnaJ, in addition to phase 2 enzymes such as hemeoxygenase-1 (HO-1), NADP(H) quinine-oxidoreductase1, and the Na(+)-independent cystine/glutamate exchanger (xCT). Treatment with D1 resulted in activation of Nrf2 and heat-shock transcription factor-1 (HSF-1) transcriptional elements, thus inducing phase 2 enzymes and HSPs, respectively. In this manner, D1 protected neuronal cells from both oxidative and endoplasmic reticulum (ER)-related stress. Additionally, D1 suppressed induction of 78 kDa glucose-regulated protein (GRP78), an ER chaperone protein, and inhibited hyperoxidation of peroxiredoxin 2 (PRX2), a molecule that is in its reduced state can protect from oxidative stress. These results suggest that D1 is a novel pro-electrophilic compound that activates both the Nrf2 and HSF-1 pathways, and may thus offer protection from oxidative and ER stress.

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A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations.

Publications

A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations.

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