title: The oncogene ATF3 is potentiated by cyclosporine A and ultraviolet light A.
abstract: Cutaneous squamous cell carcinoma (SCC) represents the most important cutaneous complication following organ transplantation. It develops mostly on sun-exposed areas. A recent study showed the role of activating transcription factor 3 (ATF3) in SCC development following treatment with calcineurin inhibitors. It has been reported that ATF3, which may act as an oncogene, is under negative calcineurin/nuclear factor of activated T cells (NFAT) control and is upregulated by calcineurin inhibitors. Still, these findings do not fully explain the preferential appearance of SCC on chronically sun-damaged skin. We analyzed the influence of UV radiation on ATF3 expression and its potential role in SCC development. We found that ATF3 is a specifically induced AP1 member in SCC of transplanted patients. Its expression was strongly potentiated by combination of cyclosporine A and UVA treatment. UVA induced ATF3 expression through reactive oxygen species-mediated nuclear factor erythroid 2-related factor 2 (NRF2) activation independently of calcineurin/NFAT inhibition. Activated NRF2 directly binds to ATF3 promoter, thus inducing its expression. These results demonstrate two mechanisms that independently induce and, when combined together, potentiate the expression of ATF3, which may then force SCC development. Taking into account the previously defined role of ATF3 in the SCC development, these findings may provide an explanation and a mechanism for the frequently observed burden on SCCs on sun-exposed areas of the skin in organ transplant recipients treated by calcineurin inhibitors.
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. Electronic address: piotr.dziunycz@usz.ch.
authors: Piotr J
authors: PJ
authors: Dziunycz
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors: Karine
authors: K
authors: Lefort
authors: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard University, Charlestown, Massachusetts, USA.
authors: Xunwei
authors: X
authors: Wu
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Sandra N
authors: SN
authors: Freiberger
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Johannes
authors: J
authors: Neu
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Nadia
authors: N
authors: Djerbi
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Guergana
authors: G
authors: Iotzowa-Weiss
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Lars E
authors: LE
authors: French
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland; Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard University, Charlestown, Massachusetts, USA.
authors: Gian-Paolo
authors: GP
authors: Dotto
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: Günther F L
authors: GFL
authors: Hofbauer
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D009924:Organ Culture Techniques; D016377:Organ Transplantation / Q000009:adverse effects; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000473:pathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D007166:Immunosuppressive Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D016572:Cyclosporine