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

Paola Arcidiacono, Catherine M. Webb, Matthew A. Brooke, Huiqing Zhou, Paul J. Delaney, Keat-Eng Ng, Diana C. Blaydon, Andrew Tinker, David P. Kelsell () and Anissa Chikh ()
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Paola Arcidiacono: Queen Mary University of London
Catherine M. Webb: Queen Mary University of London
Matthew A. Brooke: Queen Mary University of London
Huiqing Zhou: Radboud University Nijmegen Medical Centre
Paul J. Delaney: Queen Mary University of London
Keat-Eng Ng: Queen Mary University of London
Diana C. Blaydon: Queen Mary University of London
Andrew Tinker: Charterhouse Square
David P. Kelsell: Queen Mary University of London
Anissa Chikh: Queen Mary University of London

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03470-y

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