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

Aberrant transcriptional regulation is central to squamous cell carcinoma (SCC), but how related lineage transcription factors coordinate oncogenic programs is poorly understood. We show that TP73, together with TP63, is upregulated in skin SCC and is required for tumorigenesis. Using chromatin profiling, transcriptomic analysis, depletion assays, and tumor models, we find that p63 and p73 form heteromeric complexes and co-occupy distal enhancers, creating a shared regulatory framework that supports both convergent and factor-specific transcriptional outputs. Both factors sustain cell-cycle progression and restrain stress-responsive and apoptotic programs, while p63 preferentially maintains epithelial identity and cell-matrix adhesion, and p73 favors DNA replication and repair. Among shared targets, p63 and p73 co-regulate ligands of the epidermal growth factor receptor (EGFR), establishing a feedforward mitogenic signaling module. Amphiregulin is a key mediator, and its depletion impairs proliferation and tumor formation. These findings link enhancer co-occupancy by p63/p73 to signaling and squamous tumor maintenance.