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Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells
Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), is frequently overexpressed in non‐small‐cell lung cancer (NSCLC) a...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946723/ https://www.ncbi.nlm.nih.gov/pubmed/27116120 http://dx.doi.org/10.1111/cas.12957 |
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author | Takashina, Taichi Kinoshita, Ichiro Kikuchi, Junko Shimizu, Yasushi Sakakibara‐Konishi, Jun Oizumi, Satoshi Nishimura, Masaharu Dosaka‐Akita, Hirotoshi |
author_facet | Takashina, Taichi Kinoshita, Ichiro Kikuchi, Junko Shimizu, Yasushi Sakakibara‐Konishi, Jun Oizumi, Satoshi Nishimura, Masaharu Dosaka‐Akita, Hirotoshi |
author_sort | Takashina, Taichi |
collection | PubMed |
description | Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), is frequently overexpressed in non‐small‐cell lung cancer (NSCLC) and that an EZH2 inhibitor, 3‐deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH2 was recently shown to be required for the activity of histone deacetylases (HDACs) that interact with another PRC2 protein, EED. To develop a more effective epigenetic therapy for NSCLC, we determined the effects of co‐treatment with 3‐deazaneplanocin A and the HDAC inhibitor vorinostat (SAHA) in NSCLC cells. The co‐treatment synergistically suppressed the proliferation of all tested NSCLC cell lines, regardless of their epidermal growth factor receptor (EGFR) status. The synergistic effect was associated with slightly decreased histone H3 lysine 27 trimethylation, modestly increased histone acetylation, and the depletion of EZH2 and other PRC2 proteins. The co‐treatment resulted in an accumulation of p27Kip1, decrease in cyclin A, and increased apoptotic fraction in an additive/synergistic manner. Interestingly, the co‐treatment strongly suppressed EGFR signaling, not only in EGFR‐wild‐type NSCLC cells, but also in EGFR‐mutant cells, mainly through dephosphorylation of EGFR. Furthermore, the co‐treatment suppressed the in vivo tumor growth of EGFR‐mutant, EGFR–tyrosine kinase‐resistant H1975 cells more effectively than did each agent alone, without visible toxicity. These results suggest that the combined pharmacological targeting of EZH2 and HDACs may provide more effective epigenetic therapeutics for NSCLC. |
format | Online Article Text |
id | pubmed-4946723 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-49467232016-07-27 Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells Takashina, Taichi Kinoshita, Ichiro Kikuchi, Junko Shimizu, Yasushi Sakakibara‐Konishi, Jun Oizumi, Satoshi Nishimura, Masaharu Dosaka‐Akita, Hirotoshi Cancer Sci Original Articles Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), is frequently overexpressed in non‐small‐cell lung cancer (NSCLC) and that an EZH2 inhibitor, 3‐deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH2 was recently shown to be required for the activity of histone deacetylases (HDACs) that interact with another PRC2 protein, EED. To develop a more effective epigenetic therapy for NSCLC, we determined the effects of co‐treatment with 3‐deazaneplanocin A and the HDAC inhibitor vorinostat (SAHA) in NSCLC cells. The co‐treatment synergistically suppressed the proliferation of all tested NSCLC cell lines, regardless of their epidermal growth factor receptor (EGFR) status. The synergistic effect was associated with slightly decreased histone H3 lysine 27 trimethylation, modestly increased histone acetylation, and the depletion of EZH2 and other PRC2 proteins. The co‐treatment resulted in an accumulation of p27Kip1, decrease in cyclin A, and increased apoptotic fraction in an additive/synergistic manner. Interestingly, the co‐treatment strongly suppressed EGFR signaling, not only in EGFR‐wild‐type NSCLC cells, but also in EGFR‐mutant cells, mainly through dephosphorylation of EGFR. Furthermore, the co‐treatment suppressed the in vivo tumor growth of EGFR‐mutant, EGFR–tyrosine kinase‐resistant H1975 cells more effectively than did each agent alone, without visible toxicity. These results suggest that the combined pharmacological targeting of EZH2 and HDACs may provide more effective epigenetic therapeutics for NSCLC. John Wiley and Sons Inc. 2016-06-13 2016-07 /pmc/articles/PMC4946723/ /pubmed/27116120 http://dx.doi.org/10.1111/cas.12957 Text en © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Takashina, Taichi Kinoshita, Ichiro Kikuchi, Junko Shimizu, Yasushi Sakakibara‐Konishi, Jun Oizumi, Satoshi Nishimura, Masaharu Dosaka‐Akita, Hirotoshi Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells |
title | Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells |
title_full | Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells |
title_fullStr | Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells |
title_full_unstemmed | Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells |
title_short | Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells |
title_sort | combined inhibition of ezh2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946723/ https://www.ncbi.nlm.nih.gov/pubmed/27116120 http://dx.doi.org/10.1111/cas.12957 |
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