Impact of on chromatin structure and histone methylation in malignant melanoma.

The tumor suppressive role of CYLD lysine 63 deubiquitinase () is known in melanoma. To the best of our knowledge, however, the precise mechanism underlying the tumor suppressive function of has yet to be clarified. In the present study, a novel melanoma mouse model was generated, which revealed accelerated tumor growth in ‑knockout () compared with ‑wild‑type () mice. To determine the underlying molecular mechanism, mutation analysis of primary tumor‑derived cell lines from and mice was performed using RNA sequencing data. Variant calling revealed no common mutations in compared with 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 does not play a key role in DNA methylation. Chromatin accessibility and histone H3 modification assay uncovered a role of 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 melanoma cells was associated with upregulation of euchromatic histone lysine methyltransferase 2 (EHMT2). Moreover, the specific inhibitor of EHMT2, , resulted in decreased proliferation and relaxation of compact chromatin in ‑deficient melanoma cells. These results reveal a novel role of in histone methylation and chromatin packaging.