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Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer
Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver due to its prevalent overexpression and aberrant repression of tumor suppressor genes in diverse cancers. Therefore, blocking EZH2 enzyme activity may present a valid therapeutic strategy for the treatment of cancers with EZH2 overex...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751454/ https://www.ncbi.nlm.nih.gov/pubmed/26868841 http://dx.doi.org/10.1038/srep20864 |
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author | Song, Xuejiao Gao, Tiantao Wang, Ningyu Feng, Qiang You, Xinyu Ye, Tinghong Lei, Qian Zhu, Yongxia Xiong, Menghua Xia, Yong Yang, Fangfang Shi, Yaojie Wei, Yuquan Zhang, Lidan Yu, Luoting |
author_facet | Song, Xuejiao Gao, Tiantao Wang, Ningyu Feng, Qiang You, Xinyu Ye, Tinghong Lei, Qian Zhu, Yongxia Xiong, Menghua Xia, Yong Yang, Fangfang Shi, Yaojie Wei, Yuquan Zhang, Lidan Yu, Luoting |
author_sort | Song, Xuejiao |
collection | PubMed |
description | Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver due to its prevalent overexpression and aberrant repression of tumor suppressor genes in diverse cancers. Therefore, blocking EZH2 enzyme activity may present a valid therapeutic strategy for the treatment of cancers with EZH2 overexpression including breast cancers. Here, we described ZLD1039 a potent, highly selective, and orally bioavailable small molecule inhibitor of EZH2, which inhibited breast tumor growth and metastasis. ZLD1039 considerably inhibited EZH2 methyltransferase activity with nanomolar potency, decreased global histone-3 lysine-27 (H3K27) methylation, and reactivated silenced tumor suppressors connected to increased survival of patients with breast cancer. Comparable to conditional silencing of EZH2, its inhibition by ZLD1039 decreased cell proliferation, cell cycle arrest, and induced apoptosis. Comparably, treatment of xenograft-bearing mice with ZLD1039 led to tumor growth regression and metastasis inhibition. These data confirmed the dependency of breast cancer progression on EZH2 activity and the usefulness of ZLD1039 as a promising treatment for breast cancer. |
format | Online Article Text |
id | pubmed-4751454 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47514542016-02-22 Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer Song, Xuejiao Gao, Tiantao Wang, Ningyu Feng, Qiang You, Xinyu Ye, Tinghong Lei, Qian Zhu, Yongxia Xiong, Menghua Xia, Yong Yang, Fangfang Shi, Yaojie Wei, Yuquan Zhang, Lidan Yu, Luoting Sci Rep Article Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver due to its prevalent overexpression and aberrant repression of tumor suppressor genes in diverse cancers. Therefore, blocking EZH2 enzyme activity may present a valid therapeutic strategy for the treatment of cancers with EZH2 overexpression including breast cancers. Here, we described ZLD1039 a potent, highly selective, and orally bioavailable small molecule inhibitor of EZH2, which inhibited breast tumor growth and metastasis. ZLD1039 considerably inhibited EZH2 methyltransferase activity with nanomolar potency, decreased global histone-3 lysine-27 (H3K27) methylation, and reactivated silenced tumor suppressors connected to increased survival of patients with breast cancer. Comparable to conditional silencing of EZH2, its inhibition by ZLD1039 decreased cell proliferation, cell cycle arrest, and induced apoptosis. Comparably, treatment of xenograft-bearing mice with ZLD1039 led to tumor growth regression and metastasis inhibition. These data confirmed the dependency of breast cancer progression on EZH2 activity and the usefulness of ZLD1039 as a promising treatment for breast cancer. Nature Publishing Group 2016-02-12 /pmc/articles/PMC4751454/ /pubmed/26868841 http://dx.doi.org/10.1038/srep20864 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Song, Xuejiao Gao, Tiantao Wang, Ningyu Feng, Qiang You, Xinyu Ye, Tinghong Lei, Qian Zhu, Yongxia Xiong, Menghua Xia, Yong Yang, Fangfang Shi, Yaojie Wei, Yuquan Zhang, Lidan Yu, Luoting Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer |
title | Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer |
title_full | Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer |
title_fullStr | Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer |
title_full_unstemmed | Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer |
title_short | Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer |
title_sort | selective inhibition of ezh2 by zld1039 blocks h3k27methylation and leads to potent anti-tumor activity in breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751454/ https://www.ncbi.nlm.nih.gov/pubmed/26868841 http://dx.doi.org/10.1038/srep20864 |
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