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

Tatsuhiro Shibata1, Tsutomu Ohta, Kit I Tong

  • 1Cancer Genomics Project, Pathology Division, Center for Medical Genomics, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. tashibat@ncc.go.jp

Proceedings of the National Academy of Sciences of the United States of America
|September 2, 2008
PubMed

Insights

Mutations in the NRF2 gene cause its accumulation in cancer cells, leading to increased protection against oxidative stress and chemotherapy. Targeting this pathway may improve cancer treatment efficacy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • Nuclear factor E2-related factor 2 (Nrf2) regulates cytoprotective genes against oxidative stress.
  • Nrf2 is normally degraded via the Keap1-Cul3-Roc1 E3 ligase complex.
  • A two-site recognition model involving DLG and ETGE motifs governs Nrf2 ubiquitination and turnover.

Purpose of the Study:

  • Investigate the role of NRF2 mutations in human cancer.
  • Determine the functional consequences of NRF2 mutations on cancer cell survival and drug resistance.
  • Validate the Nrf2 activation model in vivo.

Main Methods:

  • Analysis of NRF2 gene mutations in human cancer patients, particularly smokers and those with squamous cell carcinoma.
  • Assessment of Nrf2 protein levels and downstream gene expression in cancer cells with NRF2 mutations.
  • siRNA-mediated knockdown of Nrf2 to evaluate sensitivity to oxidative stress and chemotherapeutic agents.
  • In vivo validation of the Keap1-Cul3-based E3 ligase mechanism.

Main Results:

  • Somatic mutations in NRF2 were identified in human cancers, especially in smokers and squamous cell carcinoma patients, correlating with poor prognosis.
  • Mutations in the DLG or ETGE motifs of Nrf2 lead to its aberrant accumulation.
  • Mutant Nrf2 cells exhibit constitutive activation of cytoprotective genes and drug efflux pumps, conferring resistance to Keap1-mediated regulation.
  • Nrf2 suppression sensitized cancer cells to oxidative stress and chemotherapy.
  • In vivo studies validated the two-site substrate recognition model for Nrf2 regulation.

Conclusions:

  • Constitutive Nrf2 activation provides cancer cells with enhanced protection against their microenvironment and anti-cancer therapies.
  • Inactivating the Nrf2 pathway presents a potential therapeutic strategy to augment current cancer treatments.
  • The study validates the two-site substrate recognition model for Nrf2 activation by the Keap1-Cul3 E3 ligase complex.

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