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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Figure 4

p53 restoration induces tumor suppression through differentiation.

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p53 restoration induces tumor suppression through differentiation. (A...
(A) Immunohistochemical analyses of papillomas of WT and p53KI/KI mice treated with DMBA/TPA for 15 weeks and tamoxifen for 15 days (3 mg/mouse/d). H&E staining (upper panels). Increased Keratin 1 expression (brown stain) is detected upon p53 restoration. Scale bar:100 μm. Original magnification, ×10. n = 7 mice per genotype. Arrowheads indicate positive staining. (B) qRT-PCR analyses of papillomas of WT and p53KI/KI mice treated with DMBA/TPA for 15 weeks and tamoxifen (Tam) for 15 days (3 mg/mouse/d). p21 expression is increased, as well as TACE, Notch1 and early differentiation markers such as Keratin 1. No induction of senescence-associated markers such as p16 and p19 is detected. *P < 0.05. n = 4 mice per genotype. (C) Western blot of the papillomas of WT and p53KI/KI mice treated with DMBA/TPA for 15 weeks and tamoxifen for 15 days (3 mg/mouse/d). p21 protein levels are increased as well as TACE, NICD, and early differentiation markers such as Keratin 1. However, no significant difference in induction of senescence-associated markers such as p16 and p19 is detected. (D) Western blot analyses of WT and p53KI/KI primary keratinocytes overexpressing H-RASV12 for 6 days after retroviral infection (Ras) and 48 hours treatment with 1 μM 4-OH tamoxifen to restore p53 expression. p21 expression is increased in p53KI/KI cells as well as TACE, NICD, and early differentiation markers such as Keratin 1.