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The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

Christina Jessen1,2, Julia K C Kreß1,2, Apoorva Baluapuri3

  • 1Department of Physiological Chemistry, University of Würzburg, Würzburg, Germany.

Oncogene
|September 26, 2020
PubMed

Insights

The transcription factor NRF2 suppresses melanoma cell pigmentation and regulates immune responses by controlling COX2 and prostaglandin E2. Its absence boosts innate immune genes, potentially impacting immune evasion in cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of oxidative stress responses.
  • NRF2's role in melanoma, where NRF2 pathway mutations are rare, is not well understood.
  • Understanding NRF2's function is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of NRF2 in melanoma, focusing on its impact on pigmentation and immune modulation.
  • To explore the link between oxidative stress, NRF2, and the induction of specific immune-related genes.
  • To determine if the NRF2-immune response connection extends to other cancer types.

Main Methods:

  • Investigated NRF2's effect on MITF (melanocyte differentiation marker) and pigmentation genes in melanoma cells.
  • Assessed NRF2's role in regulating immune-modulating genes, including cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) production.
  • Utilized NRF2-deleted melanoma cells in vivo and in vitro, alongside transcriptome analysis of human melanoma and lung adenocarcinoma datasets.

Main Results:

  • NRF2 suppresses MITF activity, reducing melanoma pigmentation.
  • NRF2 is essential for inducing COX2 and PGE2 secretion under oxidative stress (H2O2, TNFα).
  • Absence of NRF2 leads to elevated innate immune response genes (e.g., RSAD2, IFIH1) and correlates with immune evasion in human melanoma.

Conclusions:

  • NRF2 plays a dual role in melanoma by suppressing pigmentation and regulating immune responses via COX2/PGE2.
  • NRF2 deficiency enhances innate immune gene expression, suggesting a link to immune evasion.
  • The NRF2-innate immune response axis is conserved in lung adenocarcinomas, indicating broader implications in cancer.

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