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NRF3 suppresses squamous carcinogenesis, involving the unfolded protein response regulator HSPA5

Selina Gurri1, Beat Siegenthaler1, Michael Cangkrama1

  • 1Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

EMBO Molecular Medicine
|October 9, 2023
PubMed

Insights

The transcription factor NRF3 acts as a skin tumor suppressor. Its absence promotes skin cancer progression by increasing HSPA5 levels, suggesting HSPA5 inhibition as a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Epithelial skin cancers are prevalent, yet the mechanisms driving their malignancy remain unclear.
  • Understanding these mechanisms is crucial for developing effective treatments.

Purpose of the Study:

  • To identify novel tumor suppressors in skin cancer.
  • To elucidate the molecular mechanisms of skin cancer progression.
  • To explore potential therapeutic targets for epithelial skin cancers.

Main Methods:

  • Investigated NRF3 (Nuclear factor erythroid 2-related factor 3) expression in patient-derived basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) samples.
  • Utilized mouse models to assess the role of NRF3 deficiency in skin tumor development and progression.
  • Performed in vitro assays (clonogenic growth, migration, 3D invasion) with human SCC cells.
  • Identified and validated NRF3 interactors using co-immunoprecipitation and Western blotting.
  • Assessed the impact of HSPA5 (Heat shock protein family A member 5) modulation on cancer cell phenotypes and tumor growth.
  • Evaluated the efficacy of HSPA5 inhibition in preclinical models.

Main Results:

  • NRF3 protein expression was significantly downregulated in invasive BCC and SCC cells.
  • NRF3 deficiency promoted skin tumor malignant conversion, enhanced SCC cell clonogenicity, migration, and invasiveness.
  • NRF3 deficiency led to increased HSPA5 levels, which promoted cancer cell survival and migration.
  • Pharmacological inhibition or knockdown of HSPA5 reversed the malignant phenotypes of NRF3-deficient SCC cells in vitro and in vivo.
  • High HSPA5 expression correlated with NRF3 deficiency in patient SCC samples.

Conclusions:

  • NRF3 functions as a tumor suppressor in epithelial skin cancers.
  • The NRF3-HSPA5 axis is a critical regulator of skin cancer progression.
  • Targeting HSPA5 represents a promising therapeutic strategy for NRF3-deficient skin cancers.
Keywords:
HSPA5NRF3malignancyskin carcinogenesisunfolded protein response

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