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

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.

Comprehensive prediction of immune microenvironment and hot and cold tumor differentiation in cutaneous melanoma based on necroptosis-related lncRNA

“…NRIR, firstly found to be associated with melanoma by our study, was positively correlated with CYLD, MLKL, STAT1, and TNFSF10. These genes interfere with melanoma cell progression, epigenetic alterations, the microenvironment of tumor cells, and the effect on immunotherapy 16 , 41 , 42 . Besides above 3 lncRNAs, the remaining hub lncRNAs have been linked to the development of melanoma.…”

CYLD in health and disease

“…Melanoma cells of Tg( Grm1 ) Cyld −/− mice also demonstrate changes in chromatin structure. The loss of Cyld led to increased expression of the histone methyltransferase, EHMT2, associated with an increase in the histone methylation mark H3K9me2 and heterochromatin compaction ( Schott et al, 2022 ). A comparison of cells from wild-type and Cyld −/− mice confirmed a role for CYLD in chromatin structure dynamics, particularly in euchromatin maintenance.…”

“…A comparison of cells from wild-type and Cyld −/− mice confirmed a role for CYLD in chromatin structure dynamics, particularly in euchromatin maintenance. Pharmacological inhibition of EHMT2 rescued the excess heterochromatin compaction observed in Cyld −/− melanoma cells ( Schott et al, 2022 ). The mechanistic dissection of the role of CYLD in cancers apart from melanoma is likely to continue to expand and may reveal disease-specific pathogenic roles.…”

Implications of a Neuronal Receptor Family, Metabotropic Glutamate Receptors, in Cancer Development and Progression

“…We speculate that NF-κB signaling is regulated by mGluR1 through downregulation of tumor suppressor CYLD to promote melanoma growth and metastasis; however, further investigation is needed. A recent report proposed that the loss of CYLD in melanoma cells leads to the upregulation of euchromatic histone-lysine N-methyltransferase 2 (EHMT2), which is associated with the di-methylation of H3K9 and heterochromatin formation and contributes to increased tumor proliferation [ 62 ]. The SOX10 transcription factor is crucial for proper melanocyte differentiation and survival.…”