Gene expression changes in fibroblasts with constitutively active Nrf2 reflect a senescence-associated secretory phenotype (SASP). Gene expression changes in fibroblasts with constitutively active Nrf2 reflect a senescence-associated secretory phenotype (SASP)

Nrf2 is a key regulator of the cellular antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention. Here we discovered a novel role of Nrf2 as a regulator of the matrisome. Activation of Nrf2 in fibroblasts induced early onset of cellular senescence. Mechanistically, this resulted from Nrf2-mediated transcription of matrix and matrix-remodeling genes. Fibroblasts with activated Nrf2 deposited a senescence-promoting matrix, with plasminogen-activator inhibitor being the key inducer of the senescence program. In vivo, this promoted keratinocyte proliferation and re-epithelialization during wound healing, but also skin tumorigenesis. Analysis of the gene expression profile of fibroblasts with activated Nrf2 and published data sets revealed that Nrf2 activates genes characteristic for cancer-associated fibroblasts. These data identify Nrf2 as a key player in the control of the cancer-associated fibroblast phenotype and highlight the need for careful use of Nrf2-activating pharmaceuticals. Overall design: Primary fibroblasts were isolated and cultured from the skin of newborn transgenic mice with Cre-recombinase expressed in fibroblasts (Col1a2Cre). Fibroblasts from 3 mice with Cre plus a constitutively active Nrf2 (caNrf2) mutant and 3 mice with Cre only (ctrl) were used. Fibroblasts were allowed to proliferate in culture for 6 days to allow for sufficient numbers for RNA sequencing. Total RNA was isolated from cells followed by RNA-seq analysis.