[HTML][HTML] Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17
J Guinea-Viniegra, R Zenz, H Scheuch… - The Journal of …, 2012 - Am Soc Clin Investig
The Journal of clinical investigation, 2012•Am Soc Clin Investig
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 …
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 …
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.
The Journal of Clinical Investigation