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CHML is an NRF2 target gene that regulates mTOR function

Matthew Dodson1, Wujing Dai1, Annadurai Anandhan1

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA.

Molecular Oncology
|February 20, 2022
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (NRF2) promotes non-small cell lung cancer (NSCLC) by upregulating CHML (Rep2). This study reveals a novel NRF2-Rep2 pathway regulating mTOR, impacting NSCLC progression and patient survival.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Nuclear factor erythroid 2-related factor 2 (NRF2) is frequently overexpressed in non-small cell lung cancer (NSCLC).
  • NRF2 activation promotes cancer progression and treatment resistance, leading to poor patient outcomes.
  • Identifying NRF2 targets is crucial for understanding NSCLC pathogenesis.

Purpose of the Study:

  • To identify and characterize novel NRF2 target genes in NSCLC.
  • To elucidate the role of CHML (Rep2) in NSCLC progression.
  • To investigate the mechanistic link between NRF2, Rep2, and mTOR signaling in NSCLC.

Main Methods:

  • Bioinformatic analysis of The Cancer Genome Atlas (TCGA) and Oncomine databases for CHML expression.
  • Immunohistochemistry (IHC) to assess Rep2 and NRF2 protein levels in patient tissues.
  • siRNA-mediated knockdown of CHML/Rep2 in A549 NSCLC cells.
  • Assessment of cell proliferation and mTOR translocation/activation assays.

Main Results:

  • CHML was identified as a direct NRF2 target gene with an antioxidant response element (ARE) in its promoter.
  • Elevated CHML mRNA expression in lung adenocarcinoma (LUAD) correlated with decreased patient survival.
  • Rep2 protein levels were higher in lung tumors and associated with increased NRF2 levels.
  • Knockdown of CHML/Rep2 reduced NSCLC cell proliferation.
  • Rep2 regulates mTOR localization and activation at the lysosome.

Conclusions:

  • CHML (Rep2) is a novel NRF2 target gene implicated in NSCLC progression.
  • The NRF2-Rep2 axis regulates mTOR signaling, influencing cancer cell proliferation.
  • Targeting the NRF2-Rep2-mTOR pathway may offer therapeutic strategies for NSCLC.
Keywords:
CHML/REP2NRF2NSCLCmTOR

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