DNp73-induced degradation of tyrosinase links depigmentation with EMT-driven melanoma progression. (1st February 2019)

• Record Type: Journal Article
• Authors: Fürst, Katharina; Steder, Marc; Logotheti, Stella; Angerilli, Alessandro; Spitschak, Alf; Marquardt, Stephan; Schumacher, Toni; Engelmann, David; Herchenröder, Ottmar; Rupp, Ralph A.W.; Pützer, Brigitte M.
• Is Part Of: Cancer letters. Volume 442(2019)
• Page Start: 299
• Page End: 309
• Publication Date: 2019-02-01
• Subjects: Tyrosinase degradation -- p73 -- Epithelial-mesenchymal transition -- Diagnostic signature -- Melanoma progression; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.11.009
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Melanoma is an aggressive cancer with poor prognosis, requiring personalized management of advanced stages and establishment of molecular markers. Melanomas derive from melanocytes, which specifically express tyrosinase, the rate-limiting enzyme of melanin-synthesis. We demonstrate that melanomas with high levels of DNp73, a cancer-specific variant of the p53 family member p73 and driver of melanoma progression show, in contrast to their less-aggressive low-DNp73 counterparts, hypopigmentation in vivo. Mechanistically, reduced melanin-synthesis is mediated by a DNp73-activated IGF1R/PI3K/AKT axis leading to tyrosinase ER-arrest and proteasomal degradation. Tyrosinase loss triggers reactivation of the EMT signaling cascade, a mesenchymal-like cell phenotype and increased invasiveness. DNp73-induced depigmentation, Slug increase and changes in cell motility are recapitulated in neural crest-derived melanophores of Xenopus embryos, underscoring a previously unnoticed physiological role of tyrosinase as EMT inhibitor. This data provides a mechanism of hypopigmentation accompanying cancer progression, which can be exploited in precision diagnosis of patients with melanoma-associated hypopigmentation (MAH), currently seen as a favorable prognostic factor. The DNp73/IGF1R/Slug signature in colorless lesions might aid to clinically discriminate between patients with MAH-associated metastatic disease and those, where MAH is indeed a sign of regression. Highlights: In invasive melanoma tumors with DNp73 overexpression, depigmentation occurs. Hypopigmentation is due to tyrosinase ER-arrest and proteosomal degradation. Tyrosinase degradation is a consequence of an active DNp73/IGF1R/PI3K/AKT pathway. Tyrosinase loss triggers EMT marker expression and invasiveness. A DNp73/IGF1R/Slug signature is a potential marker of progression-related MAH.