Oral Presentation Australasian Society for Dermatological Research Annual Scientific Meeting 2017

YAP promotes WNT16/β-catenin signalling to drive keratinocyte proliferation in skin regeneration (#9)

Veronica Mendoza-Reinoso 1 , Susan Corley 2 , Marc Wilkins 2 , Annemiek Beverdam 1 3
  1. School of Medical Sciences, UNSW Sydney, Kensington, NSW, Australia
  2. School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Kensington, NSW, Australia
  3. School for Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia

Keratinocyte proliferation and differentiation are tightly controlled processes to maintain normal skin homeostasis, which are perturbed in skin cancer. Yes-associated protein (YAP) is a highly conserved regulator of organ size. Using a viable transgenic mouse line that expresses the constitutively active YAP2-5SA-ΔC protein mutant in the basal epidermis, we found that YAP drives β-catenin transcriptional activity to promote basal keratinocyte proliferation. To investigate the mechanism underpinning the positive regulatory interaction between YAP and β-catenin, we analysed the transcriptome of full thickness dorsal skin biopsies of P30 YAP2-5SA-ΔC and wildtype littermate mice. This revealed increased expression of the gene encoding WNT16 in YAP2-5SA-ΔC skin, which was recently identified to play a key role in promoting tumour cell survival, cancer progression and therapeutic resistance. Subsequent validation assays revealed that YAP positively regulates WNT16 expression and β-catenin activity in proliferating HaCaT keratinocytes. Furthermore, we found increased WNT16 expression levels in sparse and proliferating HaCaT keratinocytes compared to dense and quiescent cells. Depletion of Yap and Wnt16 in HaCaT keratinocytes resulted in reduced proliferation rates. Topical treatment of YAP2-5SA-ΔC skin with WNT signalling inhibitor XAV939 resulted in reduced basal keratinocyte proliferation and a mitigation of the hyperplastic epidermal abnormalities. Altogether these data support that epidermal YAP activity promotes WNT16 expression and canonical WNT signalling to promote keratinocyte proliferation in the mouse skin in vivo. This study delineates a fundamental YAP-driven mechanism that controls normal skin regeneration, and that may be perturbed in human skin cancer and other cancers displaying increased epithelial YAP activity.