Intersection of the p63 and NF‐κB pathways in epithelial homeostasis and disease

Abstract

Overexpression of ΔNp63α, a member of the p53/p63/p73 family of transcription factors, is a molecular attribute of human squamous cancers of the head and neck, lung and skin. The TP63 gene plays important roles in epidermal morphogenesis and homeostasis, regulating diverse biological processes including epidermal fate decisions and keratinocyte proliferation and survival. When overexpressed experimentally in primary mouse keratinocytes, ΔNp63α maintains a basal cell phenotype including the loss of normal calcium‐mediated growth arrest, at least in part through the activation and enhanced nuclear accumulation of the c‐rel subunit of NF‐κB (Nuclear Factor‐kappa B). Initially identified for its role in the immune system and hematopoietic cancers, c‐Rel has increasingly been associated with solid tumors and other pathologies. ΔNp63α and c‐Rel have been shown to be associated in the nuclei of ΔNp63α overexpressing human squamous carcinoma cells. Together, these transcription factors cooperate in the transcription of genes regulating intrinsic keratinocyte functions, as well as the elaboration of factors that influence the tumor microenvironment (TME). This review provides an overview of the roles of ΔNp63α and c‐Rel in normal epidermal homeostasis and elaborates on how these pathways may intersect in pathological conditions such as cancer and the associated TME.

TP63 links chromatin remodeling and enhancer reprogramming to epidermal differentiation and squamous cell carcinoma development

“…It has been shown that ΔNp63α interacts with the c-Rel subunit of nuclear factor-kappa B (NF-κB) in keratinocytes and HNSCC cells [ 192 ]. Given the central role of NF-κB in the immune system and cancer development, the cooperation between ΔNp63α and c-Rel may influence the tumor microenvironment [ 193 ]. Immunosuppressive tumor microenvironment facilitates SCC development, progression, and therapeutic resistance [ 194 , 195 ].…”

A Functional Polymorphism in Accessible Chromatin Region Confers Risk of Non-Small Cell Lung Cancer in Chinese Population

“…These evidence suggested that TP63 might be a potential target for the transcriptional regulation of rs13064999. TP63 gene, one of p53 family member, plays an important role in epidermal development and homeostasis ( 43 , 44 ). Due to two different promoters and various alternative splicing, TP63 encodes several isoforms, which are classified into two categories, TAp63 and NH2-terminal truncated (ΔNp63).…”

Dual Role of p73 in Cancer Microenvironment and DNA Damage Response

“…Paradoxically, this led to enhanced production of the thymic stromal lymphopoietin protein (TSLP), a cytokine that causes Th2 cells-mediated allergic inflammation and also induces the antigen presentation by Langerhans cells [ 152 , 153 ]. In addition, TSLP activation was mediated by exogenous expression of DNp73, concomitantly with an increase of NF-kB, a known p63/p73 coregulator [ 151 , 154 , 155 ] ( Figure 4 A). Activation of TSLP signalling promoted the Th2 immune response in breast [ 92 ] and pancreatic [ 156 ] cancers and was associated with poor prognosis [ 157 ].…”