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Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17

Juan Guinea-Viniegra1, Rainer Zenz, Harald Scheuch

  • 1Fundación Banco Bilbao Vizcaya (F-BBVA) - CNIO Cancer Cell Biology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.

The Journal of Clinical Investigation
|July 10, 2012
PubMed

Insights

Researchers discovered a FOS/p53/TACE pathway that suppresses squamous cell carcinoma (SCC) by promoting cell differentiation. Inhibiting FOS or reactivating p53/TACE may offer new targeted therapies for skin cancer.

Area of Science:

  • Oncology
  • Dermatology
  • Molecular Biology

Background:

  • Squamous cell carcinoma (SCC) is an aggressive skin cancer requiring novel therapies.
  • The FOS/AP-1 pathway's role in SCC pathogenesis is not fully understood.
  • Targeting tumor suppressor pathways is a key strategy in cancer treatment.

Purpose of the Study:

  • To identify and characterize a novel FOS/p53/TACE signaling axis involved in SCC suppression.
  • To investigate the therapeutic potential of modulating this pathway in SCC.
  • To explore the role of TACE/ADAM17 as a p53 target gene in epidermal differentiation.

Main Methods:

  • Utilized mouse models with epidermal Fos deletion.
  • Employed pharmacological inhibition of FOS/AP-1 in human SCC cell lines.
  • Analyzed p53 expression, epidermal differentiation markers, and TACE/ADAM17 activation.
  • Investigated NOTCH1 pathway activation downstream of TACE.
  • Assessed therapeutic efficacy in both mouse and human SCC models.

Main Results:

  • Epidermal Fos deletion or FOS/AP-1 inhibition induced p53 expression in SCC models.
  • p53 transcriptionally activated TACE/ADAM17, a novel target gene, promoting epidermal differentiation and tumor suppression.
  • TACE/ADAM17 was essential for NOTCH1 activation.
  • Restoring p53/TACE activity induced SCC differentiation irrespective of p53 mutation status.

Conclusions:

  • The FOS/p53/TACE axis acts as a crucial suppressor of SCC by driving differentiation.
  • FOS/AP-1 inhibition or p53/TACE reactivation represents a promising therapeutic strategy for SCC.
  • This pathway offers a potential target for developing differentiation-inducing therapies for skin cancer.

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