Activator protein-1 activity regulates epithelial tumor cell identity

Area of Science:

• Dermatology
• Molecular Biology
• Cancer Research

Background:

• The transcription factor activator protein-1 (AP-1) plays a critical role in skin biology and carcinogenesis.
• Understanding AP-1's function is crucial for developing targeted cancer therapies.

Purpose of the Study:

• To investigate the role of AP-1 transcription factors in skin tumor development and cell lineage.
• To explore the molecular mechanisms by which AP-1 regulates cell fate in skin tumors.

Main Methods:

• Generated transgenic mice using the tetracycline system to conditionally express A-FOS, a dominant-negative inhibitor of AP-1.
• Induced skin carcinogenesis and analyzed tumor development, transdifferentiation, and molecular markers.
• Performed molecular characterization of cultured keratinocytes and tumor material, including chromatin immunoprecipitation.

Main Results:

• Inhibition of AP-1 in chemically induced skin tumors prevented squamous lesions and led to sebaceous adenomas with H-ras mutations.
• AP-1 inhibition caused squamous tumors to transdifferentiate into sebaceous tumors, and AP-1 reactivation induced the reciprocal transdifferentiation.
• Tumor cells exhibited markers of both lineages, indicating multipotency, and AP-1 was found to regulate the balance between wnt/beta-catenin and hedgehog signaling pathways.

Conclusions:

• AP-1 activity is essential for maintaining squamous tumor cell identity and regulates tumor cell lineage.
• AP-1 controls cell fate decisions in skin tumors by modulating the wnt/beta-catenin and hedgehog signaling pathways.
• c-Jun, an AP-1 component, directly regulates wnt pathway genes, highlighting a key mechanism of AP-1's transcriptional control.