Abstract
The tumor suppressive role of CYLD lysine 63 deubiquitinase (CYLD) is known in melanoma. To the best of our knowledge, however, the precise mechanism underlying the tumor suppressive function of CYLD has yet to be clarified. In the present study, a novel melanoma mouse model was generated, which revealed accelerated tumor growth in Cyld-knockout (Cyld−/−) compared with Cyld-wild-type (Cyld+/+) mice. To determine the underlying molecular mechanism, mutation analysis of primary tumor-derived cell lines from Cyld+/+ and Cyld−/− mice was performed using RNA sequencing data. Variant calling revealed no common mutations in Cyld−/− compared with Cyld+/+ cells. Thus, the epigenetic processes influencing development and progression of melanoma were investigated. Initial analysis of expression pattern of known hypermethylated genes in melanoma (suppressor of cytokine signalling, methylthioadenosine phosphorylase, cadherin 1) in the presence or absence of 5′-Aza-deoxyctidine treatment revealed that CYLD does not play a key role in DNA methylation. Chromatin accessibility and histone H3 modification assay uncovered a role of CYLD in the formation of chromatin structure. Subsequent inhibitor experiments confirmed the effect of CYLD on H3K9me2 level associated with heterochromatin. Furthermore, enhanced H3K9 dimethylation in Cyld−/− melanoma cells was associated with upregulation of euchromatic histone lysine methyltransferase 2 (EHMT2). Moreover, the specific inhibitor of EHMT2, CM272, resulted in decreased proliferation and relaxation of compact chromatin in Cyld-deficient melanoma cells. These results reveal a novel role of CYLD in histone methylation and chromatin packaging.
Highlights
The deubiquitinase CYLD lysine 63 deubiquitinase (CYLD) was first described in cylindromatosis [1] and its tumor suppressive properties have been investigated in various types of cancer, such as pancreas, breast and liver cancer [2‐4]
The deubiquitinase CYLD is downregulated in different types of cancer, including hepatocellular carcinoma, breast cancer and malignant melanoma [6,35,36]
Using the melanoma mouse model Tg(Grm1) and murine cell lines generated from tumors, our previous study demonstrated the tumor suppressive function of CYLD in proliferation, migration and lymph‐ and angiogenesis [7]
Summary
The deubiquitinase CYLD lysine 63 deubiquitinase (CYLD) was first described in cylindromatosis [1] and its tumor suppressive properties have been investigated in various types of cancer, such as pancreas, breast and liver cancer [2‐4]. To the best of our knowledge, the underlying mechanisms resulting in accelerated tumor growth in Cyld‐/‐ mice have not yet been determined. Epigenetic dysregula‐ tion, including DNA methylation and post‐translational modification of histones, has been shown to be associated with cancer in a number of studies [8,9]. These changes lead to organization of DNA into chromatin and ensure genomic integrity [10]. The present study aimed to determine the underlying mechanism of accelerated melanoma development and the role of CYLD in epigenetic processes of chromatin formation and histone methylation
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