p63 and p73 drive cutaneous squamous cell carcinoma through convergent transcriptional control of EGFR signaling.

p63 and p73 jointly promote skin squamous cell carcinoma by regulating EGFR signaling through shared enhancer activity, with 50% of tumors showing upregulation.

• Why it matters: Understanding how lineage transcription factors coordinate oncogenic programs is crucial for developing targeted therapies for SCC, yet this regulatory mechanism remains unclear.
• What they did: The study used chromatin profiling, transcriptomics, depletion assays, and tumor models to demonstrate that p63 and p73 form heteromeric complexes, co-occupy enhancers, and regulate genes involved in cell cycle, stress response, and EGFR signaling.
• The result: Disrupting the EGFR ligand amphiregulin impairs tumor growth, highlighting the potential for targeting this regulatory network to treat SCC.