p63 and p73 cooperate to promote cutaneous squamous cell carcinoma through largely overlapping transcriptional programs [RNA-Seq]

Mutations in the tumor suppressor p53 are commonly found in UV-damaged skin and protect damaged epidermal cells from senescence and or oncogene-induced apoptosis, favoring cancer formation. In contrast, the other p53 family members p63 and p73 are rarely mutated in cancer and p63 is often amplified or overexpressed in lung, esophagus, and head and neck squamous cell carcinoma (SCC).

Here, we demonstrate that both p63 and p73 are required for cell proliferation in epidermal cells and in skin SCC and are overexpressed in preneoplastic lesions and in skin SCCs. p63/p73 form heterotetramers and co-occupy thousands of regulatory regions, jointly controlling a transcriptional program that promotes cell proliferation and tumorigenesis. The combination of gene knockdown with transcriptomic and epigenetic analyses revealed that p63 and p73 control a transcriptional feed-forward circuit that sustains cell proliferation.