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Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with rates of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) dramatically increasing. The overexpression of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible f...

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Autores principales: Lindsay, Cameron D., Kostiuk, Morris A., Harris, Jeff, O’Connell, Daniel A., Seikaly, Hadi, Biron, Vincent L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586065/
https://www.ncbi.nlm.nih.gov/pubmed/28878842
http://dx.doi.org/10.1186/s13148-017-0390-y
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author Lindsay, Cameron D.
Kostiuk, Morris A.
Harris, Jeff
O’Connell, Daniel A.
Seikaly, Hadi
Biron, Vincent L.
author_facet Lindsay, Cameron D.
Kostiuk, Morris A.
Harris, Jeff
O’Connell, Daniel A.
Seikaly, Hadi
Biron, Vincent L.
author_sort Lindsay, Cameron D.
collection PubMed
description BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with rates of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) dramatically increasing. The overexpression of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for the trimethylation at lysine 27 of histone 3 (H3K27me3), is associated with a poor clinical prognosis and aggressive HPV-positive phenotypes. METHODS: We utilized three EZH2 pathway inhibitors, GSK-343, DZNeP, and EPZ-5687, and tested their efficacy in two HPV-positive and two HPV-negative OPSCC cell lines. RESULTS: Treatment with GSK-343 decreased H3K27me3 in all cell lines and treatment with DZNeP decreased H3K27me3 in only HPV-negative cell lines as determined by Western blot. Cells treated with EPZ-5687 displayed no appreciable change in H3K27me3. Epigenetic effect on gene expression was measured via ddPCR utilizing 11 target probes. Cells treated with DZNeP showed the most dramatic expressional changes, with decreased EGFR in HPV-positive cell lines and an overall increase in proliferation markers in HPV-negative cell lines. GSK-343-treated cells displayed moderate expressional changes, with CCND1 increased in HPV-positive cell lines and decreased TP53 in HPV-negative SCC-1. EPZ-5687-treated cell lines displayed few expressional changes overall. Only DZNeP-treated cells displayed anti-proliferative characteristics shown in wound-healing assays. CONCLUSIONS: Our findings suggest that EZH2 inhibitors are a viable therapeutic option for the role of epigenetic effect, potentially sensitizing tumors to current chemotherapies or limiting cell differentiation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13148-017-0390-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-55860652017-09-06 Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas Lindsay, Cameron D. Kostiuk, Morris A. Harris, Jeff O’Connell, Daniel A. Seikaly, Hadi Biron, Vincent L. Clin Epigenetics Research BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with rates of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) dramatically increasing. The overexpression of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for the trimethylation at lysine 27 of histone 3 (H3K27me3), is associated with a poor clinical prognosis and aggressive HPV-positive phenotypes. METHODS: We utilized three EZH2 pathway inhibitors, GSK-343, DZNeP, and EPZ-5687, and tested their efficacy in two HPV-positive and two HPV-negative OPSCC cell lines. RESULTS: Treatment with GSK-343 decreased H3K27me3 in all cell lines and treatment with DZNeP decreased H3K27me3 in only HPV-negative cell lines as determined by Western blot. Cells treated with EPZ-5687 displayed no appreciable change in H3K27me3. Epigenetic effect on gene expression was measured via ddPCR utilizing 11 target probes. Cells treated with DZNeP showed the most dramatic expressional changes, with decreased EGFR in HPV-positive cell lines and an overall increase in proliferation markers in HPV-negative cell lines. GSK-343-treated cells displayed moderate expressional changes, with CCND1 increased in HPV-positive cell lines and decreased TP53 in HPV-negative SCC-1. EPZ-5687-treated cell lines displayed few expressional changes overall. Only DZNeP-treated cells displayed anti-proliferative characteristics shown in wound-healing assays. CONCLUSIONS: Our findings suggest that EZH2 inhibitors are a viable therapeutic option for the role of epigenetic effect, potentially sensitizing tumors to current chemotherapies or limiting cell differentiation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13148-017-0390-y) contains supplementary material, which is available to authorized users. BioMed Central 2017-09-06 /pmc/articles/PMC5586065/ /pubmed/28878842 http://dx.doi.org/10.1186/s13148-017-0390-y Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Lindsay, Cameron D.
Kostiuk, Morris A.
Harris, Jeff
O’Connell, Daniel A.
Seikaly, Hadi
Biron, Vincent L.
Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas
title Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas
title_full Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas
title_fullStr Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas
title_full_unstemmed Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas
title_short Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas
title_sort efficacy of ezh2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586065/
https://www.ncbi.nlm.nih.gov/pubmed/28878842
http://dx.doi.org/10.1186/s13148-017-0390-y
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