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


ABSTRACT:

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.

SUBMITTER: Lindsay CD 

PROVIDER: S-EPMC5586065 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

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

Lindsay Cameron D CD   Kostiuk Morris A MA   Harris Jeff J   O'Connell Daniel A DA   Seikaly Hadi H   Biron Vincent L VL  

Clinical epigenetics 20170906


<h4>Background</h4>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.<h4>Methods</h4>We utilized three EZH2 pathway in  ...[more]

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