Distinct interactors define the p63 transcriptional signature in epithelial development or cancer

Abstract

The TP63 is an indispensable transcription factor for development and homeostasis of epithelia and its derived glandular tissue. It is also involved in female germline cell quality control, muscle and thymus development. It is expressed as multiple isoforms transcribed by two independent promoters, in addition to alternative splicing occurring at the mRNA 3′-UTR. Expression of the TP63 gene, specifically the amino-deleted p63 isoform, ΔNp63, is required to regulate numerous biological activities, including lineage specification, self-renewal capacity of epithelial stem cells, proliferation/expansion of basal keratinocytes, differentiation of stratified epithelia. In cancer, ΔNp63 is implicated in squamous cancers pathogenesis of different origin including skin, head and neck and lung and in sustaining self-renewal of cancer stem cells. How this transcription factor can control such a diverse set of biological pathways is central to the understanding of the molecular mechanisms through which p63 acquires oncogenic activity, profoundly changing its down-stream transcriptional signature. Here, we highlight how different proteins interacting with p63 allow it to regulate the transcription of several central genes. The interacting proteins include transcription factors/regulators, epigenetic modifiers, and post-transcriptional modifiers. Moreover, as p63 depends on its interactome, we discuss the hypothesis to target the protein interactors to directly affect p63 oncogenic activities and p63-related diseases.

Identification of Muc1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas

“…S4B ), supporting potential involvement of the MUC1-C/STAT1 autoinductive pathway ( 39 ). ∆Np63 is transcribed from a promoter in the third intron of the TP63 gene ( 31 ), which was of interest in that a promoter-like signature (PLS) in this region contains a potential STAT binding motif ( Fig. 4C ).…”

p63: a crucial player in epithelial stemness regulation

“…The ΔNp63 isoforms are mainly involved in maintaining the self-renewing capacity of progenitor cells in different epithelia [ 29 – 32 ]. TAp63 and ΔNp63 variants are typically and differentially expressed in epithelial tissues and their appendixes [ 33 , 34 ]. For example, ΔNp63 (mainly ΔNp63α) is the most predominant isoform expressed in the skin, vagina and esophageal mucosa.…”

“…1C ). As a result, p63-deficient mice lack epidermis and other stratified epithelia [ 20 , 34 ]. The mice are born alive but die shortly after birth because of severe dehydration, and manifest dramatic developmental defects, affecting particularly their limbs and skin [ 19 ].…”

Serine and one-carbon metabolism sustain non-melanoma skin cancer progression

“…Thus, immunotherapy with PD-1 blockade has emerged as the latest standard-of-care treatment strategy developed for advanced and metastatic SCCs. A crucial step of NMSC and HNSCC development is the alteration of normal epidermal cell proliferation; indeed, several studies report that cancer cells can adapt their metabolism to achieve this effect [46][47][48][49][50][51][52]. The term onecarbon metabolism (OCM) refers to a complex metabolic pathway involved in the generation of one-carbon units (hydroxymethyl groups) used by the cells for the biosynthesis of fundamental anabolic precursors, for cellular redox homeostasis and for methylation reactions [53].…”