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NRF2 regulates EGF stability through OTUD4 in lung adenocarcinoma

Shuming Hu1, Yuan Yuan2, Ruihan Yan1

  • 1Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Biochemical and Biophysical Research Communications
|March 22, 2024
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (NRF2) regulates Epidermal Growth Factor (EGF) stability in lung adenocarcinoma. NRF2 activates OTUD4, which deubiquitinates and stabilizes EGF, promoting tumor progression.

Area of Science:

  • Molecular Biology
  • Oncology
  • Gene Regulation

Background:

  • Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor crucial for cellular antioxidant response and tumor progression.
  • NRF2 influences various cellular processes, including metabolism and biosynthesis, and its role in lung adenocarcinoma (LUAD) is significant.

Purpose of the Study:

  • To elucidate the novel mechanism by which NRF2 regulates Epidermal Growth Factor (EGF) stability in lung adenocarcinoma.
  • To investigate the role of deubiquitinases in the NRF2-EGF regulatory pathway.

Main Methods:

  • Modulation of NRF2 expression in LUAD cells (A549).
  • Identification and analysis of EGF ubiquitination status.
  • Prediction and validation of deubiquitinase (OTUD4) interaction with NRF2.
  • Analysis of NRF2 binding to the OTUD4 promoter and its transcriptional activation.
  • Correlation analysis of NRF2 and OTUD4 expression in LUAD patient data.

Main Results:

  • NRF2 modulates EGF expression at the protein level in LUAD cells.
  • EGF was identified as a ubiquitinated protein, and OTUD4 showed the highest correlation with NRF2.
  • NRF2 directly binds to the OTUD4 promoter, transcriptionally activating OTUD4 expression.
  • Activated OTUD4 promotes EGF deubiquitination and enhances EGF stability.
  • A significant correlation between OTUD4 and NRF2 expression was observed in LUAD patients.

Conclusions:

  • NRF2 enhances EGF stability through the deubiquitinase OTUD4 in lung adenocarcinoma.
  • This novel regulatory axis highlights a potential therapeutic target for LUAD treatment.
  • The findings reveal a new mechanism linking NRF2, OTUD4, and EGF in cancer progression.
Keywords:
EGFLung adenocarcinomaNRF2OTUD4Ubiquitination

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