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

Abstract

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. image Non‐melanoma skin cancers (NMSCs) are the most frequently diagnosed cancers in humans. Here we show that NRF3 acts as a potent tumor‐suppressing protein in the skin by controlling the unfolded protein response regulator HSPA5, which we identified as promising target for the treatment of NMSC. NRF3 protein is downregulated in human NMSC. Loss of NRF3 promotes the malignancy and tumorigenesis of skin cancer cells. HSPA5 levels are enhanced in NRF3 ‐KO cells and in invasively growing skin cancer cells. HSPA5 inhibition or knock‐down reverts the high malignancy of NRF3‐deficient cells. Pharmacological inhibition of HSPA5 offers promising therapeutic opportunities for the treatment of NMSC.