p63 is a key regulator of iRHOM2 signalling in the keratinocyte stress response

Abstract

Hyperproliferative keratinocytes induced by trauma, hyperkeratosis and/or inflammation display molecular signatures similar to those of palmoplantar epidermis. Inherited gain-of-function mutations in RHBDF2 (encoding iRHOM2) are associated with a hyperproliferative palmoplantar keratoderma and squamous oesophageal cancer syndrome (termed TOC). In contrast, genetic ablation of rhbdf2 in mice leads to a thinning of the mammalian footpad, and reduces keratinocyte hyperproliferation and migration. Here, we report that iRHOM2 is a novel target gene of p63 and that both p63 and iRHOM2 differentially regulate cellular stress-associated signalling pathways in normal and hyperproliferative keratinocytes. We demonstrate that p63–iRHOM2 regulates cell survival and response to oxidative stress via modulation of SURVIVIN and Cytoglobin, respectively. Furthermore, the antioxidant compound Sulforaphane downregulates p63–iRHOM2 expression, leading to reduced proliferation, inflammation, survival and ROS production. These findings elucidate a novel p63-associated pathway that identifies iRHOM2 modulation as a potential therapeutic target to treat hyperproliferative skin disease and neoplasia.

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

“…ΔNp63α is the prominent isoform of the TP63 gene expressed in keratinocytes and basal cells of diverse epithelia [ 19 – 21 ] and various SCCs [ 2 ]. ΔNp63α promotes SCC development through regulating different target genes, including cell growth and proliferation [ 22 , 23 ], extracellular matrix (ECM)–receptor interaction [ 24 ], cell adhesion [ 25 – 27 ], glucose metabolism [ 28 , 29 ], anti-oxidant defense [ 30 , 31 ], DNA damage repair [ 32 , 33 ], terminal differentiation [ 34 , 35 ], and inflammation and angiogenesis [ 36 – 41 ] (Fig. 2 ).…”

iRhom2: An Emerging Adaptor Regulating Immunity and Disease

“…Similar to ADAM17 iRhom2 levels are regulated transcriptionally. iRhom2 is a p63 transcription factor target gene in keratinocytes [ 51 ], is induced in response to exposure to lipopolysaccharides (LPS) or viral infections in macrophages [ 9 , 43 , 44 ] and induced in the liver post bile duct ligation [ 52 ]. It may also be regulated through proteasomal mediated degradation.…”

The molecular, cellular and pathophysiological roles of iRhom pseudoproteases

“…Additionally, keratinocytes from patients with TOC show an upregulation of K16 levels, alluding to its potential contribution to palmoplantar thickening. It was also described that iRhom2 can be regulated by p63, a transcription factor implicated in epithelial development [70]. TOC keratinocytes are resistant to p63-induced cell death induced by ultraviolet B rays, indicating a complex relationship between iRhom2 and p63 in keratinocyte biology and their response to stress.…”