Opposing roles for calcineurin and ATF3 in squamous skin cancer

Abstract

Calcineurin inhibitors such as cyclosporin A (CsA) are the mainstay of immunosuppressive treatment for organ transplant recipients. Squamous cell carcinoma (SCC) of the skin is a major complication of treatment with these drugs, with a 65 to 100-fold higher risk than in the normal population1. By contrast, the incidence of basal cell carcinoma (BCC), the other major keratinocyte-derived tumour of the skin, of melanoma and of internal malignancies increases to a significantly lesser extent1. Here we report that genetic and pharmacological suppression of calcineurin/nuclear factor of activated T cells (NFAT) function promotes tumour formation in mouse skin and in xenografts, in immune compromised mice, of H-rasV12 (also known as Hras1)-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the ‘enlarged’ AP-1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumours, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.

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Figure 1: Calcineurin/NFAT inhibition promotes keratinocyte tumour formation.
Figure 2: Calcineurin/NFAT signalling negatively controls ATF3 expression.
Figure 3: ATF3 upregulation enhances keratinocyte tumour formation and suppresses cancer cell senescence.
Figure 4: Calcineurin inhibition and increased ATF3 enhance cancer initiating cell populations.

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Acknowledgements

We thank P. Khavari, S. Kitajima, N. Clipstone and G. Crabtree for gift of retroviruses, W. Austen for human skin material, C. Brisken and C. Missero for careful reading of the manuscript, and E. Castillo for sequencing of the ras and p53 genes. This work was supported by grants from NIH (AR054856 and AR39190), the Swiss National Foundation (311003A-122281/1), Oncosuisse (OCS-02361-02-2009), the European Union (Epistem, Sixth Framework Program, LSHB-CT-2005-019067) and, in part, by a grant to S.C. by the Korean Government Foundation (KRF-2007-013-E00044) and to G.F.L.H. by the Olga-Mayenfisch-Stiftung.

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B-C.N., P.D, S.C, Y.B., K.L. and G.F.L.H. performed research and analysed data; X.W. and G.P.D. designed and performed research, analysed data and wrote the manuscript.

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Correspondence to G. Paolo Dotto.

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Wu, X., Nguyen, B., Dziunycz, P. et al. Opposing roles for calcineurin and ATF3 in squamous skin cancer. Nature 465, 368–372 (2010). https://doi.org/10.1038/nature08996

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