Journal
DEVELOPMENTAL CELL
Volume 46, Issue 2, Pages 145-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2018.06.012
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Funding
- Swiss National Science Foundation [310030_ 132884, 31003A_169204]
- Wilhelm Sander-Stiftung
- Swiss Cancer League [KFS-3474-08-2014]
- Banting postdoctoral fellowship
- Swiss National Science Foundation (SNF) [31003A_169204] Funding Source: Swiss National Science Foundation (SNF)
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Nrf2 is a key regulator of the antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention and promotion of tissue repair. Here we show, however, that activation of Nrf2 in fibroblasts induces cellular senescence. Using a combination of transcriptomics, matrix proteomics, chromatin immunoprecipitation and bioinformatics we demonstrate that fibroblasts with activated Nrf2 deposit a senescence-promoting matrix, with plasminogen activator inhibitor-1 being a key inducer of the senescence program. In vivo, activation of Nrf2 in fibroblasts promoted re-epithelialization of skin wounds, but also skin tumorigenesis. The pro-tumorigenic activity is of general relevance, since Nrf2 activation in skin fibroblasts induced the expression of genes characteristic for cancer-associated fibroblasts from different mouse and human tumors. Therefore, activated Nrf2 qualifies as a marker of the cancer-associated fibroblast phenotype. These data highlight the bright and the dark sides of Nrf2 and the need for time-controlled activation of this transcription factor.
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