The foggy world(s) of p63 isoform regulation in normal cells and cancer

Abstract

The p53 family member p63 exists as two major protein variants (TAp63 and ΔNp63) with distinct expression patterns and functional properties. Whilst downstream target genes of p63 have been studied intensively, how p63 variants are themselves controlled has been relatively neglected. Here, we review advances in understanding ΔNp63 and TAp63 regulation, highlighting their distinct pathways. TAp63 has roles in senescence and metabolism, and in germ cell genome maintenance, where it is activated post‐transcriptionally by phosphorylation cascades after DNA damage. The function and regulation of TAp63 in mesenchymal and haematopoietic cells is less clear but may involve epigenetic control through DNA methylation. ΔNp63 functions to maintain stem/progenitor cells in various epithelia and is overexpressed in squamous and certain other cancers. ΔNp63 is transcriptionally regulated through multiple enhancers in concert with chromatin modifying proteins. Many signalling pathways including growth factors, morphogens, inflammation, and the extracellular matrix influence ΔNp63 levels, with inconsistent results reported. There is also evidence for reciprocal regulation, including ΔNp63 activating its own transcription. ΔNp63 is downregulated during cell differentiation through transcriptional regulation, while post‐transcriptional events cause proteasomal degradation. Throughout the review, we identify knowledge gaps and highlight discordances, providing potential explanations including cell‐context and cell–matrix interactions. Identifying individual p63 variants has roles in differential diagnosis and prognosis, and understanding their regulation suggests clinically approved agents for targeting p63 that may be useful combination therapies for selected cancer patients. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Inhibition of HDAC and Signal Transduction Pathways Induces Tight Junctions and Promotes Differentiation in p63-Positive Salivary Duct Adenocarcinoma

“…HDAC inhibitors downregulate p63 expression [ 12 ]. To investigate whether HDAC inhibitors affect expression of p63 and the TJ proteins, A253 cells were treated with the HDAC inhibitors trichostatin A (TSA) and quisinostat (JNJ -26481585) in the presence of EW-7197 and SP600125.…”

“…Cancer cells with mesenchymal traits increase cell migration and invasion, resulting in cancer metastasis [ 11 ]. The human TP63 gene is aligned with histone H3 acetylated at lysine 27 (H3K27Ac) [ 12 ]. p63/p40 (ΔNp63) is used for diagnostic utility in the histologic differentiation of salivary gland tumors [ 13 ].…”

Tissue-specific expression of p73 and p63 isoforms in human tissues

“…Both p73 and p63 genes have two promoters (P1 and P2) that give rise to isoforms with distinct transcriptional programs [ 1 , 5 , 9 , 20 – 23 ]. Isoforms transcribed from P1 contain a full-length transactivation (TA) domain [ 1 , 5 ], while isoforms transcribed from P2 have a truncated TA (∆N) domain [ 5 , 20 ].…”

THE SPLICING FACTOR PTBP1 REPRESSES TP63 γ ISOFORM PRODUCTION IN SQUAMOUS CELL CARCINOMA

“…The functions of p63 are therefore strongly dependent on the regulation of the production of the different 5’ and 3’ isoforms in a tissue-specific manner. Despite the acknowledged importance of the differential role of the p63 C-terminal isoforms, the regulation of the multiple alternative splicing events involved in p63 pre-mRNA maturation remains unaddressed (Pokorná et al 2021).…”