title: Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17.
abstract: Squamous cell carcinomas (SCCs) are heterogeneous and aggressive skin tumors for which innovative, targeted therapies are needed. Here, we identify a p53/TACE pathway that is negatively regulated by FOS and show that the FOS/p53/TACE axis suppresses SCC by inducing differentiation. We found that epidermal Fos deletion in mouse tumor models or pharmacological FOS/AP-1 inhibition in human SCC cell lines induced p53 expression. Epidermal cell differentiation and skin tumor suppression were caused by a p53-dependent transcriptional activation of the metalloprotease TACE/ADAM17 (TNF-α-converting enzyme), a previously unknown p53 target gene that was required for NOTCH1 activation. Although half of cutaneous human SCCs display p53-inactivating mutations, restoring p53/TACE activity in mouse and human skin SCCs induced tumor cell differentiation independently of the p53 status. We propose FOS/AP-1 inhibition or p53/TACE reactivating strategies as differentiation-inducing therapies for SCCs.
authors: Fundación Banco Bilbao Vizcaya (F-BBVA) - CNIO Cancer Cell Biology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors: Juan
authors: J
authors: Guinea-Viniegra
authors: Rainer
authors: R
authors: Zenz
authors: Harald
authors: H
authors: Scheuch
authors: María
authors: M
authors: Jiménez
authors: Latifa
authors: L
authors: Bakiri
authors: Peter
authors: P
authors: Petzelbauer
authors: Erwin F
authors: EF
authors: Wagner
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D016760:Proto-Oncogene Proteins c-fos; D016159:Tumor Suppressor Protein p53; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse