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The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells
The histone methyltransferase EZH2 plays a role in maintenance of the stem component of cancer, and its overexpression and/or mutation typically drives tumor aggressiveness, drug resistance and patients’ poor prognosis. In this study, we use mouse and human medulloblastoma stem-like cells belonging...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620277/ https://www.ncbi.nlm.nih.gov/pubmed/28978137 http://dx.doi.org/10.18632/oncotarget.19782 |
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author | Miele, Evelina Valente, Sergio Alfano, Vincenzo Silvano, Marianna Mellini, Paolo Borovika, Diana Marrocco, Biagina Po, Agnese Besharat, Zein Mersini Catanzaro, Giuseppina Battaglia, Giuseppe Abballe, Luana Zwergel, Clemens Stazi, Giulia Milite, Ciro Castellano, Sabrina Tafani, Marco Trapencieris, Peteris Mai, Antonello Ferretti, Elisabetta |
author_facet | Miele, Evelina Valente, Sergio Alfano, Vincenzo Silvano, Marianna Mellini, Paolo Borovika, Diana Marrocco, Biagina Po, Agnese Besharat, Zein Mersini Catanzaro, Giuseppina Battaglia, Giuseppe Abballe, Luana Zwergel, Clemens Stazi, Giulia Milite, Ciro Castellano, Sabrina Tafani, Marco Trapencieris, Peteris Mai, Antonello Ferretti, Elisabetta |
author_sort | Miele, Evelina |
collection | PubMed |
description | The histone methyltransferase EZH2 plays a role in maintenance of the stem component of cancer, and its overexpression and/or mutation typically drives tumor aggressiveness, drug resistance and patients’ poor prognosis. In this study, we use mouse and human medulloblastoma stem-like cells belonging to the Sonic Hedgehog subgroup (SHH MB-SLCs) and demonstrate that genetic suppression of EZH2 reduces the level of its histone mark H3K27me3 and lowers proliferation and self-renewal. We designed an EZH2 inhibitor (EZH2i) as a simplified analog of EPZ005687 and GSK2816126, MC3629, and we tested its biological activity in SHH MB-SLCs. Pharmacological inhibition of EZH2 impairs SHH MB cells proliferation and self-renewal, and induces apoptosis in vitro. Finally, we generated xenograft MB-SLCs orthotopic tumors in nude mice to test MC3629 in vivo. In treated mice, we observed impairment of tumor growth, together with induction of apoptosis and reduction of proliferation and stemness. Overall, these findings describe EZH2 as a druggable target in MB and provide insight into the biological activity of MC3629 as an EZH2i. |
format | Online Article Text |
id | pubmed-5620277 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56202772017-10-03 The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells Miele, Evelina Valente, Sergio Alfano, Vincenzo Silvano, Marianna Mellini, Paolo Borovika, Diana Marrocco, Biagina Po, Agnese Besharat, Zein Mersini Catanzaro, Giuseppina Battaglia, Giuseppe Abballe, Luana Zwergel, Clemens Stazi, Giulia Milite, Ciro Castellano, Sabrina Tafani, Marco Trapencieris, Peteris Mai, Antonello Ferretti, Elisabetta Oncotarget Research Paper The histone methyltransferase EZH2 plays a role in maintenance of the stem component of cancer, and its overexpression and/or mutation typically drives tumor aggressiveness, drug resistance and patients’ poor prognosis. In this study, we use mouse and human medulloblastoma stem-like cells belonging to the Sonic Hedgehog subgroup (SHH MB-SLCs) and demonstrate that genetic suppression of EZH2 reduces the level of its histone mark H3K27me3 and lowers proliferation and self-renewal. We designed an EZH2 inhibitor (EZH2i) as a simplified analog of EPZ005687 and GSK2816126, MC3629, and we tested its biological activity in SHH MB-SLCs. Pharmacological inhibition of EZH2 impairs SHH MB cells proliferation and self-renewal, and induces apoptosis in vitro. Finally, we generated xenograft MB-SLCs orthotopic tumors in nude mice to test MC3629 in vivo. In treated mice, we observed impairment of tumor growth, together with induction of apoptosis and reduction of proliferation and stemness. Overall, these findings describe EZH2 as a druggable target in MB and provide insight into the biological activity of MC3629 as an EZH2i. Impact Journals LLC 2017-08-02 /pmc/articles/PMC5620277/ /pubmed/28978137 http://dx.doi.org/10.18632/oncotarget.19782 Text en Copyright: © 2017 Miele et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Miele, Evelina Valente, Sergio Alfano, Vincenzo Silvano, Marianna Mellini, Paolo Borovika, Diana Marrocco, Biagina Po, Agnese Besharat, Zein Mersini Catanzaro, Giuseppina Battaglia, Giuseppe Abballe, Luana Zwergel, Clemens Stazi, Giulia Milite, Ciro Castellano, Sabrina Tafani, Marco Trapencieris, Peteris Mai, Antonello Ferretti, Elisabetta The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells |
title | The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells |
title_full | The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells |
title_fullStr | The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells |
title_full_unstemmed | The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells |
title_short | The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells |
title_sort | histone methyltransferase ezh2 as a druggable target in shh medulloblastoma cancer stem cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620277/ https://www.ncbi.nlm.nih.gov/pubmed/28978137 http://dx.doi.org/10.18632/oncotarget.19782 |
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