title: Investigation of EZH2 pathways for novel epigenetic treatment strategies in oropharyngeal cancer.
abstract: BACKGROUND
  In recent decades, the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rising worldwide as a result of increasing oncogenic human papillomavirus (HPV) infections in the oropharynx. EZH2 is an epigenetic regulatory protein associated with tumor aggressiveness and negative survival outcomes in several human cancers. We aimed to determine the role of EZH2 as a potential therapeutic epigenetic target in HPV-positive and negative OPSCC.
  
  
  METHODS
  The expression of EZH2 was measured by immunohistochemistry (IHC) and droplet digital PCR (ddPCR) in 2 HPV-positive and 2 HPV-negative cell lines. The cell lines were then cultured and treated with one of 3 EZH2 epigenetic inhibitors (3-deazaneplanocin A, GSK-343 and EPZ005687) or DMSO (control). Following 2, 4 and 7 days of treatment, cells were analyzed and compared by gene expression, cell survival and proliferation assays.
  
  
  RESULTS
  EZH2 targeting resulted in greater inhibition of growth and survival in HPV-positive compared to HPV-negative cells lines. The expression profile of genes important in OPSCC also differed according to HPV-positivity for Ki67, CCND1, MET and PTEN/PIK3CA, but remained unchanged for EGFR, CDKN2A and p53.
  
  
  CONCLUSIONS
  Inhibition of EZH2 has anti-tumorigenic effects on OPSCC cells in culture that is more pronounced in HPV-positive cell lines. EZH2 is a promising epigenetic target for the treatment of OPSCC.
authors: Division of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Alberta, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.
authors: Sherif
authors: S
authors: Idris
authors: Division of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Alberta, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.
authors: Cameron
authors: C
authors: Lindsay
authors: Division of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Alberta, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.|Alberta Head & Neck Centre for Oncology and Reconstruction, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.
authors: Morris
authors: M
authors: Kostiuk
authors: Division of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Alberta, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.
authors: Colin
authors: C
authors: Andrews
authors: Division of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Alberta, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.
authors: David W J
authors: DW
authors: Côté
authors: Division of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Alberta, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.|Alberta Head & Neck Centre for Oncology and Reconstruction, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.
authors: Daniel A
authors: DA
authors: O'Connell
authors: Division of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Alberta, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.|Alberta Head & Neck Centre for Oncology and Reconstruction, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.
authors: Jeffrey
authors: J
authors: Harris
authors: Division of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Alberta, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.|Alberta Head & Neck Centre for Oncology and Reconstruction, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.
authors: Hadi
authors: H
authors: Seikaly
authors: Division of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Alberta, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7. vbiron@ualberta.ca.|Alberta Head & Neck Centre for Oncology and Reconstruction, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7. vbiron@ualberta.ca.
authors: Vincent L
authors: VL
authors: Biron
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000628:therapy / Q000821:virology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D057890:Epigenomics; D006801:Humans; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology; D009959:Oropharyngeal Neoplasms / Q000235:genetics* / Q000628:therapy / Q000821:virology*; D030361:Papillomavirus Infections / Q000235:genetics* / Q000628:therapy / Q000821:virology*; D016133:Polymerase Chain Reaction; D011728:Pyridones / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C578195:EPZ005687; C586265:GSK343; D007191:Indazoles; D011728:Pyridones; C048460:3-deazaneplanocin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D000241:Adenosine
keywords: 3-deazaneplanocin A; EPZ005687; EZH2; Epigenetics; GSK-343; Histone methylation; Oropharyngeal cancer; Squamous cell carcinoma