Opposing roles for calcineurin and ATF3 in squamous skin cancer.
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 population. 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 extent. 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-ras(V12) (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.
Wu
Xunwei
X
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Nguyen
Bach-Cuc
BC
Dziunycz
Piotr
P
Chang
Sungeun
S
Brooks
Yang
Y
Lefort
Karine
K
Hofbauer
Günther F L
GF
Dotto
G Paolo
GP
D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D019703:Calcineurin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D016572:Cyclosporine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D065095:Calcineurin Inhibitors; D050778:NFATC Transcription Factors; D016159:Tumor Suppressor Protein p53; D016572:Cyclosporine; D019703:Calcineurin