p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis

Abstract

The role of p63 in cancer has been an area of intense debate and controversy. Is TP63 (which encodes p63) a tumour suppressor gene or an oncogene? This debate is partly due to the complexity of the gene. There are several p63 isoforms - some with tumour suppressive functions and others with oncogenic functions. In this Opinion article, we focus on the recent advances in understanding p63 biology and its roles in cancer. In this regard, we discuss the role of p63 in multiple stem cell compartments, ageing, in the response to DNA damage and in DNA repair. Finally, we highlight the importance of understanding the interactions between all three p53 family members and the potential impact of this knowledge on cancer therapy and regenerative medicine.

Figure 1. p53, p63 and p73 sequence and structural similarity

TP63 and TP73 are composed of multiple isoforms that can be placed in two categories: the TA isoforms, which contain an acidic transactivation (TA) domain that is encoded by the first three exons; and the ΔN isoforms, which lack this amino-terminal domain. Shown for both TP63 and TP73 are the α-, β- and γ-isoforms, which are determined by alternative splicing of the carboxyl terminus. TP53, TP63 and TP73 share sequence nucleotide similarity in three regions: the TA domain, the DNA binding domain (DBD) and the oligomerization domain (OD). Numbers shown represent shared percentage identity between TP53, TP63 and TP73. Only the p63α and p73α isoforms contain a sterile alpha motif (SAM) domain in both the TA and the ΔN isoforms.

Figure 2. Extensive interaction between p53 and TAp63 in response to DNA damage

a Subsequent to DNA damage, which can be induced through treatment with ionizing radiation, doxorubicin or cisplatin, p53, TAp63 and TAp73 activate downstream transcriptional targets to induce multiple cell fates. p53, TAp63 and TAp73 can transcriptionally activate cyclin-dependent kinase inhibitor 1A (CDKN1A; which encodes p21) individually to induce cell cycle arrest. b | Subsequent to DNA damage, TAp63 and TAp73 are required in complex with p53 to transcriptionally activate genes that are involved in apoptosis, including BCL-2 binding component 3 (BBC3; also known as PUMA), BCL-2-associated X protein (BAX), PMAIP1 (also known as NOXA) and PERP. c | p53, TAp63 and TAp73 transactivate genes that are involved in metabolism. TAp63 transactivates sirtuin 1 (SIRT1), STK11 (also known as LKB1) and PRKAA2 (also known as AMPKA2) to regulate glucose and lipid metabolism. TAp73 transactivates cytochrome c oxidase subunit IV isoform 1 (COX4I1), which is a subunit of the mitochondrial multimeric enzyme that executes the last step in aerobic respiration. p53 transactivates C12ORF5 (also known as TIGAR) and glutaminase 2 (GLS2), which are crucial for its function as a tumour suppressor.

Figure 3. Mechanisms used by TAp63 to suppress metastasis

TAp63 suppresses metastasis by transcriptionally activating metastasis suppressor genes or microRNAs, including DICER1, mir-130b and basic helix–loop–helix family, member e41 (BHLHE41; also known as SHARP1). TAp63 is also crucial to induce other, as yet unknown, target genes (indicated by a question mark) that suppress metastasis and that are involved in integrin recycling. Mutant p53 (p53^MUT) and transforming growth factor-β (TGFβ) can inhibit the metastasis-suppressive activities of the TAp63 isoforms.

Figure 4. TAp63 and ΔNp63 are expressed in discrete areas of the dermis and epidermis

A cross-section through a hair follicle and the surrounding epidermis is shown. TAp63 is expressed in the dermal sheath and the dermal papilla of the hair follicle in dermal stem cells, which are known as skin-derived precursor cells (SKPs). TAp63 transcriptionally regulates cyclin-dependent kinase inhibitor 1C (CDKN1C; which encodes p57) to maintain SKPs in quiescence. ΔNp63 is not expressed in SKPs but is expressed in the basal cells of the epidermis and is crucial for the proliferation and terminal differentiation of these cells.