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2017 ; 9
(ä): 95
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Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human
papillomavirus-negative oropharyngeal squamous cell carcinomas
#MMPMID28878842
Lindsay CD
; Kostiuk MA
; Harris J
; O'Connell DA
; Seikaly H
; Biron VL
Clin Epigenetics
2017[]; 9
(ä): 95
PMID28878842
show ga
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.
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