Activation of Nrf2 in keratinocytes causes chloracne (MADISH)‐like skin disease in mice

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis. Cancer Res; 75(22); 4817-29. Ó2015 AACR.

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“…1D and Supplementary Fig. S1C), consistent with the enlarged sebaceous glands in mice with stronger Nrf2 activation (3,19).…”

Section: Nrf2 Activation Has a Mild Tumor-preventive Effect In A Modesupporting

confidence: 70%

Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations

et al. 2015

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“…On mating these mice with transgenic mice expressing Cre recombinase under control of a keratin 5 (K5) promoter, the STOP cassette is deleted in keratinocytes, resulting in expression of caNrf2 in all layers of the epidermis and in the hair follicles. The double mutant mice (designated K5Cre-CMVcaNrf2 mice) develop progressive epidermal thickening and hyperkeratosis as well as enlarged sebaceous glands 9,26 . However, only very minor phenotypic abnormalities are present in neonatal mice 9 .…”

Section: Resultsmentioning

confidence: 99%

A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

et al. 2014

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The Nrf2 transcription factor controls the expression of genes involved in the antioxidant defense system. Here, we identified Nrf2 as a novel regulator of desmosomes in the epidermis through the regulation of microRNAs. On Nrf2 activation, expression of miR-29a and miR-29b increases in cultured human keratinocytes and in mouse epidermis. Chromatin immunoprecipitation identified the Mir29ab1 and Mir29b2c genes as direct Nrf2 targets in keratinocytes. While binding of Nrf2 to the Mir29ab1 gene activates expression of miR-29a and -b, the Mir29b2c gene is silenced by DNA methylation. We identified desmocollin-2 (Dsc2) as a major target of Nrf2-induced miR-29s. This is functionally important, since Nrf2 activation in keratinocytes of transgenic mice causes structural alterations of epidermal desmosomes. Furthermore, the overexpression of miR-29a/b or knockdown of Dsc2 impairs the formation of hyper-adhesive desmosomes in keratinocytes, whereas Dsc2 overexpression has the opposite effect. These results demonstrate that a novel Nrf2-miR-29-Dsc2 axis controls desmosome function and cutaneous homeostasis.

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“…Total cellular RNA isolation, purification using the MinElute Kit (QIAGEN, Hilden, Germany), cDNA synthesis, and quantitative RT-PCR (qRT-PCR) were described previously (6). Primers used are listed in Table I.…”

Section: Rna Isolation and Quantitative Rt-pcrmentioning

confidence: 99%

“…This causes enhanced drug resistance, increased survival under stress conditions, and hyperproliferation of the tumor cells as a result of an increased abundance of multidrug-resistance proteins, ROSdetoxifying enzymes, and metabolic enzymes (2,3). Recent studies from our laboratory also demonstrated that chronic activation of Nrf2 in keratinocytes causes hyperkeratosis, epidermal thickening due to keratinocyte hyperproliferation, cutaneous inflammation, and sebocyte hyperplasia (4)(5)(6). Therefore, we searched for soluble mediators that are controlled by Nrf2 and may affect cell proliferation and/or inflammation.…”

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confidence: 98%

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

Kurinna

Muzumdar

Köhler

et al. 2016

The Journal of Immunology

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The Nrf2 transcription factor is well known for its cytoprotective functions through regulation of genes involved in the detoxification of reactive oxygen species or toxic compounds. Therefore, activation of Nrf2 is a promising strategy for the protection of tissues from various types of insults and for cancer prevention. However, recent studies revealed a proinflammatory activity of activated Nrf2 and a stimulating effect on epithelial cell proliferation, but the underlying mechanisms of action and the responsible target genes are largely unknown. Using a combination of gene expression profiling, chromatin immunoprecipitation, and targeted proteomics via selected reaction monitoring, we show that the gene encoding the proinflammatory cytokine IL-36γ is a novel direct target of Nrf2 in keratinocytes and hepatocytes in vitro and in vivo. As a consequence, upregulation of IL-36γ expression occurred upon genetic or pharmacological activation of Nrf2 in the epidermis and in the normal and regenerating liver. Functional in vitro studies demonstrate that IL-36γ directly stimulates proliferation of keratinocytes. In particular, it induces expression of keratinocyte mitogens in fibroblasts, suggesting that the Nrf2–IL-36γ axis promotes keratinocyte proliferation through a double paracrine loop. These results provide mechanistic insight into Nrf2 action in the control of inflammation and cell proliferation through regulation of a proinflammatory cytokine with a key function in various inflammatory diseases.

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Activation of Nrf2 in keratinocytes causes chloracne (MADISH)‐like skin disease in mice

Cited by 83 publications

References 44 publications

Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations

Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations

A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

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