NRF3 suppresses squamous carcinogenesis, involving the unfolded protein response regulator HSPA5.
HSPA5
NRF3
malignancy
skin carcinogenesis
unfolded protein response
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
08 11 2023
08 11 2023
Historique:
revised:
05
09
2023
received:
28
03
2023
accepted:
15
09
2023
medline:
9
11
2023
pubmed:
9
10
2023
entrez:
9
10
2023
Statut:
ppublish
Résumé
Epithelial skin cancers are extremely common, but the mechanisms underlying their malignant progression are still poorly defined. Here, we identify the NRF3 transcription factor as a tumor suppressor in the skin. NRF3 protein expression is strongly downregulated or even absent in invasively growing cancer cells of patients with basal and squamous cell carcinomas (BCC and SCC). NRF3 deficiency promoted malignant conversion of chemically induced skin tumors in immunocompetent mice, clonogenic growth and migration of human SCC cells, their invasiveness in 3D cultures, and xenograft tumor formation. Mechanistically, the tumor-suppressive effect of NRF3 involves HSPA5, a key regulator of the unfolded protein response, which we identified as a potential NRF3 interactor. HSPA5 levels increased in the absence of NRF3, thereby promoting cancer cell survival and migration. Pharmacological inhibition or knock-down of HSPA5 rescued the malignant features of NRF3-deficient SCC cells in vitro and in preclinical mouse models. Together with the strong expression of HSPA5 in NRF3-deficient cancer cells of SCC patients, these results suggest HSPA5 inhibition as a treatment strategy for these malignancies in stratified cancer patients.
Identifiants
pubmed: 37807968
doi: 10.15252/emmm.202317761
pmc: PMC10630885
doi:
Substances chimiques
Endoplasmic Reticulum Chaperone BiP
0
NFE2L3 protein, human
0
HSPA5 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e17761Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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