Loss of CYLD accelerates melanoma development and progression in the Tg(Grm1) melanoma mouse model

Abstract

The deubiquitinase cylindromatosis (CYLD) is a well-known tumor suppressor, found to be down regulated in many cancer types including breast cancer, colon carcinoma and malignant melanoma. CYLD is suppressed in human melanoma cells by the transcriptional repressor SNAIL1 leading to an increase of their proliferative, invasive and migratory potential. To gain additional insights into the distinct function of this tumor suppressor gene a new mouse model Tg(Grm1)Cyld−/− was generated. Herewith, we demonstrate that Cyld-deficiency leads to earlier melanoma onset and accelerated tumor growth and metastasis in the GRM1 melanoma mouse model. First, RNA sequencing data revealed a potential role of CYLD in the regulation of genes involved in proliferation, migration and angiogenesis. Experiments using cell lines generated from both primary and metastatic melanoma tissue of Tg(Grm1) Cyld−/− and Tg(Grm1) Cyld+/+ mice confirmed that loss of CYLD enhances the proliferative and migratory potential, as well as the clonogenicity in vitro. Moreover, we could show that Cyld-knockout leads to increased vasculogenic mimicry and enhanced (lymph-) angiogenesis shown by tube formation assays, immunohistochemistry and mRNA expression analyses. In summary, our findings reveal new functional aspects of CYLD in the process of (lymph-) angiogenesis and demonstrate its importance in the early process of melanoma progression.

CYLD-mutant cylindroma-like basaloid carcinoma of the anus: a genetically and morphologically distinct class of HPV-related anal carcinoma

“…In mouse models, inactivation of CYLD in the epidermis promotes sebaceous hyperplasia and proliferations with basaloid and sebaceous components [ 32 ], while global knockout mice are prone to developing cutaneous papillomas [ 12 ]. Loss of CYLD activity has been correlated with more aggressive behavior in cutaneous squamous cell carcinoma [ 33 ], melanoma [ 13 , 34 ], pancreatic carcinoma [ 35 ], and hepatocellular carcinoma [ 15 ]. In addition, gene expression profiling of CYLD -mutant tumors has shown dysregulated tropomyosin kinase signaling, which has been suggested as a potential target for therapy [ 36 , 37 ].…”

The role of ubiquitination in tumorigenesis and targeted drug discovery

“…181 The loss of CYLD accelerates tumorigenesis and triggers cisplatin resistance in melanoma and oral squamous cell carcinoma. 182,183 Thus, CYLD is considered a molecular switch for the ubiquitination of AKT and determines the localization and activation of AKT during cancer progression.…”

An Update on the Role of Ubiquitination in Melanoma Development and Therapies

“…Recently, the role of CYLD was investigated in a murine model (Grm1) for spontaneous melanoma development [ 100 ]. The authors demonstrated that CYLD-knockout mice displayed increased tumor growth compared to wild-type mice.…”

“…The authors demonstrated that CYLD-knockout mice displayed increased tumor growth compared to wild-type mice. CYLD-deficiency appeared to favor lymphatic angiogenesis [ 100 ].…”