CYLD Inhibits the Development of Skin Squamous Cell Tumors in Immunocompetent Mice

• Published in: International journal of molecular sciences 2021-07, Vol.22 (13), p.6736
• Main Authors: Alameda, Josefa P, García-García, Verónica A, López, Silvia, Hernando, Ana, Page, Angustias, Navarro, Manuel, Moreno-Maldonado, Rodolfo, Paramio, Jesús M, Ramírez, Ángel, García-Fernández, Rosa A, Casanova, María Llanos
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Apoptosis; Cancer; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell - blood supply; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell differentiation; Cell Differentiation - genetics; Cell proliferation; Cell Proliferation - genetics; Cells, Cultured; Deubiquitinating Enzyme CYLD - genetics; Deubiquitinating Enzyme CYLD - metabolism; Genes; Genes, Tumor Suppressor; Immunocompetence; Immunohistochemistry; Inflammation; Keratin; Keratinocytes; Keratinocytes - drug effects; Keratinocytes - pathology; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Neovascularization, Pathologic - genetics; NF-kappa B - metabolism; NF-κB protein; Phorbol Esters - toxicity; Proteins; Rodents; Skin cancer; Skin Neoplasms - blood supply; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Transgenic animals; Transgenic mice; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-α; Tumor suppressor genes; Tumorigenesis; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22136736

Cylindromatosis (CYLD) is a deubiquitinase (DUB) enzyme that was initially characterized as a tumor suppressor of adnexal skin tumors in patients with CYLD syndrome. Later, it was also shown that the expression of functionally inactive mutated forms of CYLD promoted tumor development and progression of non-melanoma skin cancer (NMSC). However, the ability of wild-type CYLD to inhibit skin tumorigenesis in vivo in immunocompetent mice has not been proved. Herein, we generated transgenic mice that express the wild type form of CYLD under the control of the keratin 5 (K5) promoter (K5-CYLDwt mice) and analyzed the skin properties of these transgenic mice by WB and immunohistochemistry, studied the survival and proliferating characteristics of primary keratinocytes, and performed chemical skin carcinogenesis experiments. As a result, we found a reduced activation of the nuclear factor kappa B (NF-κB) pathway in the skin of K5-CYLDwt mice in response to tumor necrosis factor-α (TNF-α); accordingly, when subjected to insults, K5-CYLDwt keratinocytes are prone to apoptosis and are protected from excessive hyperproliferation. Skin carcinogenesis assays showed inhibition of tumor development in K5-CYLDwt mice. As a mechanism of this tumor suppressor activity, we found that a moderate increase in CYLD expression levels reduced NF-κB activation, which favored the differentiation of tumor epidermal cells and inhibited its proliferation; moreover, it decreased tumor angiogenesis and inflammation. Altogether, our results suggest that increased levels of CYLD may be useful for anti-skin cancer therapy.