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Impact of CYLD on chromatin structure and histone methylation in malignant melanoma
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 rev...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973957/ https://www.ncbi.nlm.nih.gov/pubmed/35293595 http://dx.doi.org/10.3892/ijmm.2022.5122 |
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author | Schott, Mandy Kappelmann-Fenzl, Melanie Fischer, Stefan Fernandez-Barrena, Maite G. Pineda-Lucena, Antonio Ávila, Matías A. Kuphal, Silke Bosserhoff, Anja-Katrin |
author_facet | Schott, Mandy Kappelmann-Fenzl, Melanie Fischer, Stefan Fernandez-Barrena, Maite G. Pineda-Lucena, Antonio Ávila, Matías A. Kuphal, Silke Bosserhoff, Anja-Katrin |
author_sort | Schott, Mandy |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8973957 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-89739572022-04-05 Impact of CYLD on chromatin structure and histone methylation in malignant melanoma Schott, Mandy Kappelmann-Fenzl, Melanie Fischer, Stefan Fernandez-Barrena, Maite G. Pineda-Lucena, Antonio Ávila, Matías A. Kuphal, Silke Bosserhoff, Anja-Katrin Int J Mol Med Articles 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. D.A. Spandidos 2022-05 2022-03-15 /pmc/articles/PMC8973957/ /pubmed/35293595 http://dx.doi.org/10.3892/ijmm.2022.5122 Text en Copyright: © Schott et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Schott, Mandy Kappelmann-Fenzl, Melanie Fischer, Stefan Fernandez-Barrena, Maite G. Pineda-Lucena, Antonio Ávila, Matías A. Kuphal, Silke Bosserhoff, Anja-Katrin Impact of CYLD on chromatin structure and histone methylation in malignant melanoma |
title | Impact of CYLD on chromatin structure and histone methylation in malignant melanoma |
title_full | Impact of CYLD on chromatin structure and histone methylation in malignant melanoma |
title_fullStr | Impact of CYLD on chromatin structure and histone methylation in malignant melanoma |
title_full_unstemmed | Impact of CYLD on chromatin structure and histone methylation in malignant melanoma |
title_short | Impact of CYLD on chromatin structure and histone methylation in malignant melanoma |
title_sort | impact of cyld on chromatin structure and histone methylation in malignant melanoma |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973957/ https://www.ncbi.nlm.nih.gov/pubmed/35293595 http://dx.doi.org/10.3892/ijmm.2022.5122 |
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