p63 and p73 regulate convergent and factor-specific transcriptional programs in cutaneous squamous cell carcinoma

Aberrant transcriptional regulation is a defining feature of squamous cell carcinoma (SCC), yet how lineage transcription factors coordinate shared and factor-specific oncogenic programs remains poorly understood. Although TP63 (p63) is frequently amplified in SCC, the contribution of its paralog TP73 (p73) has remained unclear. Here we show that p73, together with p63, is upregulated in skin SCC and is required for tumorigenesis. Mechanistically, p63 and p73 form heteromeric complexes and co-occupy distal enhancer elements, establishing a shared chromatin regulatory framework. Integration of chromatin and transcriptomic profiling reveals that this common enhancer landscape supports both convergent and divergent transcriptional outputs. Both factors cooperatively sustain core proliferation but also exert regulatory biases, with p63 preferentially reinforcing epithelial lineage circuits and p73 contributing to DNA replication and stress-associated pathways. Among shared downstream targets, p63/p73 co-regulation of multiple epidermal growth factor receptor (EGFR) ligands establishes a feed-forward signaling module that amplifies mitogenic signaling. Amphiregulin emerges as a dominant functional mediator, and its depletion phenocopies key aspects of p63/p73 loss, including impaired proliferation and tumor formation. Together, these findings support a model in which shared enhancer occupancy by p63 and p73 drives cooperative and factor-specific transcriptional programs, linking chromatin regulation to signaling and tumor maintenance.