The p63 protein belongs to the p53 family of transcription factors and is considered a master regulator of stem cell maintenance and differentiation of epithelial tissues as well as a central player in oocyte fate determination. For years the role of p63 in cancer has been a subject of debate, as there are p63 isoforms with oncogenic functions while others have a tumor suppressive role.

In this image of the month, we highlight the transcription factor p63 and its contradictory roles in cancer. As we can see it is expressed in the nuclei of human keratinocytes (HaCaT) and interestingly, variation in protein expression levels is observed among cells. As a member of the p53 family, and due to the sequence and structural similarity to p53 (one of the most mutated genes in cancer), it would have been easy to attribute the role of tumor suppressor to p63 as well.

However, the TP63 gene encodes, by alternative promoters and by alternative splicing, different isoforms of p63 that actually antagonize each other. The TAp63 isoforms activate transcriptional target genes that induce apoptosis and cell cycle arrest in response to DNA damage, similar to the role of p53, thus acting as tumor suppressors (Su et al, 2014). Outside the context of cancer, it has been demonstrated that these isoforms protect the germline by promoting the apoptosis of oocytes following DNA damage (Kerr et al, 2012).

On the other hand, the DeltaNp63 isoforms are amino-terminally truncated isoforms that act antagonistically to TAp63 by competing for DNA binding sites and by inhibiting the functions of p53 and TAp63 (Su et al, 2014). These isoforms promote cell growth and protect cells from apoptosis thus assuming a tumor promoting role in the context of cancer. More specifically, increased expression of DeltaNp63 is a molecular feature commonly observed in distinct types of squamous cell carcinoma (Melino et al, 2015) and high abundance of DeltaNp63 correlates with poor prognosis in cancer patients. During epidermal development, the DeltaNp63 and the TAp63 isoforms are critical players in epithelial morphogenesis by regulating the stem cell proliferation and differentiation (Li et al, 2023).

To add an extra level of complexity, the ratio between the different p63 isoforms, (and other p53 family members) in different cellular contexts can affect not only the physiological functions of p63 but also its role in cancer.