NRF3 suppresses squamous carcinogenesis, involving the unfolded protein response regulator HSPA5
An "EMBO Molecular Medicine" paper by the Werner group (IMHS) shows that the NRF3 protein is downregulated or even absent in invasively growing cancer cells of patients with epithelial skin cancer, resulting in enhanced malignancy due to the upregulation of the unfolded protein response regulator HSPA5.
Epithelial skin cancers are the most frequently diagnosed malignancies in humans, but the mechanisms underlying their malignant progression are still poorly defined. Gurri et al. identified NRF3 as a potent tumor-suppressing protein in the skin. NRF3 protein expression was strongly down-regulated or even absent in invasively growing cancer cells of patients with epithelial skin cancers. NRF3 deficiency resulted in the upregulation of HSPA5, a key regulator of the unfolded protein response, which was identified as a potential NRF3 interactor. The increased levels of HSPA5 promoted cancer cell malignancy and tumorigenesis.
Pharmacological inhibition or knock-down of HSPA5 rescued the malignant features of NRF3-deficient cancer cells in vitro and in preclinical mouse models. Together with the strong expression of HSPA5 in NRF3-deficient tumor cells of skin cancer patients, these results suggest HSPA5 inhibition as a treatment strategy for these malignancies in stratified patients.
Link to the publication in external page "EMBO Molecular Medicine".