Epigenetic regulation of iASPP-p63 feedback loop in cutaneous squamous cell carcinoma.

Epigenetic regulation of iASPP-p63 feedback loop in cutaneous squamous cell carcinoma.

J Invest Dermatol. 2019 Jan 30;:

Authors: Robinson DJ, Patel A, Purdie KJ, Wang J, Rizvi H, Hufbauer M, Ostano P, Akgül B, Chiorino G, Harwood C, Bergamaschi D

Abstract
Keratinocyte skin cancer, comprising cutaneous squamous (cSCC) and basal cell carcinoma, is the most common malignancy in the UK. P53 is frequently mutated in cSCC. iASPP is a key inhibitor of p53 and NF-kB signalling pathways and has been documented as highly expressed in several types of human cancer. We have previously identified an autoregulatory feedback loop between iASPP and p63, which is critical in epidermal homeostasis. We hypothesised a potential role for dysregulation of this axis in the pathogenesis of keratinocyte malignancies. Immunostaining of 116 cSCC clinical samples revealed increased iASPP and ΔNp63 expression but also highlighted a significant alteration of iASPP cellular localisation, with consequent deregulation of its function. Expression patterns, functionality, gene and microRNA expression analysis were further investigated in 10 cSCC cell lines. Our data suggest that whilst direct effects of iASPP and p63 upon each other's expression are maintained in cSCC, epigenetic dysregulation of the feedback loop occurs at the microRNA level by a previously unreported mechanism controlling p63 expression. We demonstrate that this autoregulatory feedback loop controls cell migration in cSCC by blocking EMT and promoting proliferation and provides future directions for clinical biomarker and therapeutic target discovery in cutaneous SCC.

PMID: 30710576 [PubMed - as supplied by publisher]

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