Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17
Juan Guinea-Viniegra, … , Peter Petzelbauer, Erwin F. Wagner
Juan Guinea-Viniegra, … , Peter Petzelbauer, Erwin F. Wagner
Published July 9, 2012
Citation Information: J Clin Invest. 2012;122(8):2898-2910. https://doi.org/10.1172/JCI63103.
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Research Article Oncology

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

Juan Guinea-Viniegra, Rainer Zenz, Harald Scheuch, María Jiménez, Latifa Bakiri, Peter Petzelbauer, Erwin F. Wagner

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