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Decoupling of Nrf2 Expression Promotes Mesenchymal State Maintenance in Non-Small Cell Lung Cancer.

ABSTRACT: Epithelial mesenchymal transition is a common mechanism leading to metastatic dissemination and cancer progression. In an effort to better understand this process we found an intersection of Nrf2/NLE2F2 (Nrf2), epithelial mesenchymal transition (EMT), and metabolic alterations using multiple in vitro and in vivo approaches. Nrf2 is a key transcription factor controlling the expression of redox regulators to establish cellular redox homeostasis. Nrf2 has been shown to exert both cancer inhibitory and stimulatory activities. Using multiple isogenic non-small cell lung cancer (NSCLC) cell lines, we observed a reduction of Nrf2 protein and activity in a prometastatic mesenchymal cell state and increased reactive oxygen species. Knockdown of Nrf2 promoted a mesenchymal phenotype and reduced glycolytic, TCA cycle and lipogenic output from both glucose and glutamine in the isogenic cell models; while overexpression of Nrf2 promoted a more epithelial phenotype and metabolic reactivation. In both Nrf2 knockout mice and in NSCLC patient samples, Nrf2low was co-correlated with markedly decreased expression of glycolytic, lipogenic, and mesenchymal RNAs. Conversely, Nrf2high was associated with partial mesenchymal epithelial transition and increased expression of metabolic RNAs. The impact of Nrf2 on epithelial and mesenchymal cancer cell states and metabolic output provide an additional context to Nrf2 function in cancer initiation and progression, with implications for therapeutic inhibition of Nrf2 in cancer treatment.

SUBMITTER: Haley JA

PROVIDER: S-EPMC6826656 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Decoupling of Nrf2 Expression Promotes Mesenchymal State Maintenance in Non-Small Cell Lung Cancer.

Haley John A JA Ruiz Christian F CF Montal Emily D ED Wang Daifeng D Haley John D JD Girnun Geoffrey D GD

Cancers 20191002 10

Epithelial mesenchymal transition is a common mechanism leading to metastatic dissemination and cancer progression. In an effort to better understand this process we found an intersection of Nrf2/NLE2F2 (Nrf2), epithelial mesenchymal transition (EMT), and metabolic alterations using multiple in vitro and in vivo approaches. Nrf2 is a key transcription factor controlling the expression of redox regulators to establish cellular redox homeostasis. Nrf2 has been shown to exert both cancer inhibitory ...[more]

PMID: 31581742

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Project description:BackgroundNuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs.Methods and findingsHere we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps.ConclusionsThis is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.

Dataset Information

Decoupling of Nrf2 Expression Promotes Mesenchymal State Maintenance in Non-Small Cell Lung Cancer.

Publications

Decoupling of Nrf2 Expression Promotes Mesenchymal State Maintenance in Non-Small Cell Lung Cancer.

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