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Cited by 728Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressGlutathione Transferases and Polymorphisms

Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy

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Shibata, Tatsuhiro, Ohta, Tsutomu, Tong, Kit I., Kokubu, Akiko, Odogawa, Reiko, Tsuta, Koji, Asamura, Hisao, Yamamoto, Masayuki +1 more·2008·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0806268105PMC PMC2533230
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Abstract

The nuclear factor E2-related factor 2 (Nrf2) is a master transcriptional activator of genes encoding numerous cytoprotective enzymes that are induced in response to environmental and endogenously derived oxidative/electrophilic agents. Under normal, nonstressed circumstances, low cellular concentrations of Nrf2 are maintained by proteasomal degradation through a Keap1-Cul3-Roc1-dependent mechanism. A model for Nrf2 activation has been proposed in which two amino-terminal motifs, DLG and ETGE, promote efficient ubiquitination and rapid turnover; known as the two-site substrate recognition/hinge and latch model. Here, we show that in human cancer, somatic mutations occur in the coding region of NRF2 , especially among patients with a history of smoking or suffering from squamous cell carcinoma; in the latter case, this leads to poor prognosis. These mutations specifically alter amino acids in the DLG or ETGE motifs, resulting in aberrant cellular accumulation of Nrf2. Mutant Nrf2 cells display constitutive induction of cytoprotective enzymes and drug efflux pumps, which are insensitive to Keap1-mediated regulation. Suppression of Nrf2 protein levels by siRNA knockdown sensitized cancer cells to oxidative stress and chemotherapeutic reagents. Our results strongly support the contention that constitutive Nrf2 activation affords cancer cells with undue protection from their inherently stressed microenvironment and anti-cancer treatments. Hence, inactivation of the Nrf2 pathway may represent a therapeutic strategy to reinforce current treatments for malignancy. Congruously, the present study also provides in vivo validation of the two-site substrate recognition model for Nrf2 activation by the Keap1-Cul3-based E3 ligase.

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  • NRF2 is mutationally activated in 10-30% of different solid tumors including liver, lung, stomach, colon and other cancers.

    “NRF2 is mutationally activated in 10–30% of different solid tumors including liver, lung, stomach, colon and other cancers and mutations typically disrupt the interaction between NRF2 and its E3 ligase KEAP1 (Kelch Like ECH Associated Protein 1) directly or by impeding KEAP1 co-factors CUL3 (Cullin 3) and CAND1 (Cullin Associated and Neddylation Dissociated 1) [2,5,6,7,8].”

    From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [7]

    The Results report NRF2 mutations in 10.7% of primary lung tumors and 25% of primary head-and-neck tumors, supporting the stated range for those cancers. The paper does not establish a 10–30% mutation rate for liver, stomach, or colon cancers, so the claim extends beyond the tumors studied. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Mutations in the NRF2 pathway typically disrupt the interaction between NRF2 and KEAP1 directly or by impeding KEAP1 co-factors CUL3 and CAND1.

    “NRF2 is mutationally activated in 10–30% of different solid tumors including liver, lung, stomach, colon and other cancers and mutations typically disrupt the interaction between NRF2 and its E3 ligase KEAP1 (Kelch Like ECH Associated Protein 1) directly or by impeding KEAP1 co-factors CUL3 (Cullin 3) and CAND1 (Cullin Associated and Neddylation Dissociated 1) [2,5,6,7,8].”

    From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [7]

    The Results (page unavailable) show that cancer-associated NRF2 mutations can impair binding to KEAP1, and the Discussion describes KEAP1 as part of a Cullin3-based E3 ligase. Our copy does not report mutations that impede CUL3 or CAND1, so it does not support that alternative mechanism. Its reported mutation frequencies concern lung and head-and-neck cancers, not the full range of tumors listed in the citing sentence. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Mutations to NRF2 and its regulator KEAP1 have been found in cancer cells, supporting the supposition that antioxidant genes are pivotal in tumor progression.

    “In this regard, mutations to NRF2 and its regulator KEAP1 have been found in cancer cells, supporting the supposition that antioxidant genes are pivotal in tumor progression59–62.”

    From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [59]

  • Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance.

    “Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, thereby leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance (e.g., chemoresistance) (Figure 8) [161,162,163,164,165,166,167,168,169,170,171].”

    From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [162]

  • Aberrant Nrf2 expression and poor prognosis have been revealed in a wide range of cancers, including lung, esophageal, breast, bladder, liver, prostate, and colorectal carcinomas.

    “numerous studies have revealed aberrant Nrf2 expression and poor prognosis in a wide range of cancers, including, among others, lung, esophageal, breast, bladder, liver, prostate, and colorectal carcinomas [161,162,169,170,171,173,174]”

    From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [162]

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Authors
Shibata, T., Ohta, T., Tong, K. I., Kokubu, A., Odogawa, R., Tsuta, K., Asamura, H., Yamamoto, M., & Hirohashi, S.
Affiliations
  • National Cancer Center Research Institute (JP)
  • University of Tsukuba (JP)
  • *Cancer Genomics Project, Pathology Division,
  • National Cancer Center Hospital (JP)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2008-09-09
Volume
105
Issue
36
Pages
13568-13573
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0806268105
PMC
PMC2533230
OpenAlex
W1998560601
Cited by
728
References
8
Citations by year
2026: 25 · 2025: 27 · 2024: 33 · 2023: 35 · 2022: 37 · 2021: 36 · 2020: 60 · 2019: 36 · 2018: 40 · 2017: 50 · 2016: 55 · 2015: 53 · 2014: 46 · 2013: 67 · 2012: 50
FWCI
10.41
Type
journal article
Language
en
Update notices
correction (2009-06-23)
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Japan Science and Technology Corporation
  • Ministry of Education, Culture, Sports, Science and Technology
  • National Institute of Biomedical Innovation
  • Exploratory Research for Advanced Technology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
Keywords
Nrf2, somatic mutations, Nrf2 activation, squamous cell carcinoma, smoking, drug efflux pumps, oxidative stress resistance, chemoresistance, cancer prognosis
MeSH terms
Kelch-Like ECH-Associated Protein 1, Antineoplastic Agents, Base Sequence, Humans, Models, Molecular, Mutation, Neoplasms, Protein Binding, Substrate Specificity, Transcription, Genetic, Down-Regulation, Gene Expression Regulation, Neoplastic, Protein Structure, Tertiary, Oxidative Stress, Active Transport, Cell Nucleus, Cullin Proteins, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2

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