Abstract
BackgroundHead 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.MethodsWe 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.ResultsTreatment 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.ConclusionsOur 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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with rates of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) dramatically increasing
The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has significantly increased over the past decade [3,4,5]. This increase in OPSCC is due to the exposure to high-risk serotypes of the human papillomavirus (HPV), with anywhere from 40 to 90% of OPSCC classified as HPV positive [4,5,6,7,8,9]
We investigated the effects of three enhancer of zeste homolog 2 (EZH2) pathway inhibitors: two S-adenosylmethionine (SAM)-competitive inhibitors (GSK-343 and EPZ-5687) and an S-adenosylhomocysteine (SAH)-hydrolase inhibitor (DZNeP) in HPV-positive (SCC-47 and SCC-104) and HPV-negative (SCC-1 and SCC-9) HNSCC cell lines
Summary
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 incidence of oropharyngeal squamous cell carcinoma (OPSCC) has significantly increased over the past decade [3,4,5]. This increase in OPSCC is due to the exposure to high-risk serotypes of the human papillomavirus (HPV), with anywhere from 40 to 90% of OPSCC classified as HPV positive [4,5,6,7,8,9]. Clinical prognoses for HPV-positive OPSCCs are significantly better than HPV-negative cancers, as tumors display increased susceptibility to surgical intervention, chemotherapeutics, Lindsay et al Clinical Epigenetics (2017) 9:95 and radiotherapies [10,11,12,13]. These clinical differences are associated with distinct differences in HPV-positive OPSCC host gene expression and epigenetic profiles relative to HPV-negative cancers [14,15,16,17,18,19,20]
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