Targeting of Epigenetic Modifier EZH2 in Oropharyngeal Squamous Cell Carcinomas

• Author / Creator

  Lindsay, Cameron D

• Head and neck squamous cell carcinoma (HNSCC) is the 6th most prevalent cancer worldwide with rates of human papillomavirus (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. Three EZH2 pathway inhibitors; GSK-343, DZNeP, and EPZ-5687, were tested for efficacy in two HPV-positive (SCC-47 and SCC-104) and two HPV-negative (SCC-1 and SCC-9) HNSCC cell lines. Treatment with GSK-343 decreased H3K27me3 in all cell lines, whereas DZNeP decreased H3K27me3 in 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 via wound-healing assay. Our findings suggest that EZH2 inhibitors remain a viable therapeutic option for the role of epigenetic effect, potentially limiting cell differentiation.

• Subjects / Keywords

  • Biology
  • Cancer
  • Epigenetics
  • Oropharynx
  • EZH2

• Graduation date

  Spring 2018

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3CN6ZF0H

• License

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