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NRF2 Activation in Cancer: From DNA to Protein

Erica W Cloer1,2, Dennis Goldfarb2,3, Travis P Schrank2,4

  • 1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.

Cancer Research
|February 15, 2019
PubMed

Insights

Alterations in the NRF2 pathway are common in lung cancers, promoting tumor growth and resistance to treatment. Understanding these changes could lead to new cancer therapies targeting NRF2 activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genomics

Background:

  • The Kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway is frequently altered in cancer.
  • These alterations are enriched in lung and upper airway cancers, affecting 6.3% of patient samples across 226 studies.
  • Constitutive NRF2 activation drives cancer hallmarks like oxidative stress resistance, proliferation, and metabolic reprogramming, correlating with poor prognosis and treatment resistance.

Purpose of the Study:

  • To review the diverse mechanisms underlying NRF2 activation in cancer.
  • To organize these mechanisms according to the central dogma of molecular biology: DNA, RNA, and protein levels.
  • To highlight the potential for novel therapeutic targets based on a comprehensive understanding of NRF2 activation.

Main Methods:

  • Literature review of The Cancer Genome Atlas (TCGA) data.
  • Analysis of genomic, epigenetic, mRNA splicing, mRNA stability, posttranslational modifications, and protein-protein interaction data.
  • Categorization of NRF2 activation mechanisms by molecular level (DNA, RNA, protein).

Main Results:

  • NRF2 pathway alterations are prevalent in various cancers, particularly lung and upper airway types.
  • Activated NRF2 signaling promotes key cancer-promoting processes and is linked to adverse patient outcomes.
  • Mechanisms of NRF2 activation span DNA alterations, RNA processing, and protein modifications.

Conclusions:

  • NRF2 activation is a critical oncogenic mechanism with diverse regulatory pathways.
  • A thorough understanding of these mechanisms is essential for developing targeted NRF2-based cancer therapies.
  • Despite its prevalence and impact, effective FDA-approved drugs targeting NRF2 in cancer are still lacking.

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