title: The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma.
abstract: BACKGROUND
  HPV infection causes cervical cancer, mediated in part by the degradation of Scribble via the HPV E6 oncoprotein. Recently, Scribble has been shown to be an important regulator of the Hippo signaling cascade. Deregulation of the Hippo pathway induces an abnormal cellular transformation, epithelial to mesenchymal transition, which promotes oncogenic progression. Given the recent rise in oropharyngeal HPV squamous cell carcinoma we sought to determine if Hippo signaling components are implicated in oropharyngeal squamous cell carcinoma.
  
  
  METHODS
  Molecular and cellular techniques including immunoprecipiations, Western blotting and immunocytochemistry were used to identify the key Hippo pathway effector Yes-Associated Protein (YAP)﻿1. Oropharyngeal tissue was collected from CO2laser resections, and probed with YAP1 antibody in tumor and pre-malignant regions of HPV positive OPSCC tissue.
  
  
  RESULTS
  This study reveals that the Scribble binding protein Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) forms a complex with YAP. Further, the NOS1APa and NOS1APc isoforms show differential association with activated and non-activated YAP, and impact cellular proliferation. Consistent with deregulated Hippo signaling in OPSCC HPV tumors, we see a delocalization of Scribble and increased nuclear accumulation of YAP1 in an HPV-positive OPSCC.
  
  
  CONCLUSIONS
  Our preliminary data indicates that NOS1AP isoforms differentially associate with YAP1, which, together with our previous findings, predicts that loss of YAP1 enhances cellular transformation. Moreover, YAP1 is highly accumulated in the nucleus of HPV-positive OPSCC, implying that Hippo signaling and possibly NOS1AP expression are de-regulated in OPSCC. Further studies will help determine if NOS1AP isoforms, Scribble and Hippo components will be useful biomarkers in OPSCC tumor biology.
authors.affiliation: Division of Otolaryngology, Department of Surgery, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada.
authors.forename: Faisal
authors.initials: F
authors.lastname: Alzahrani
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Leanne
authors.initials: L
authors.lastname: Clattenburg
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Muruganandan
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Bullock
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: MacIsaac
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Wigerius
authors.affiliation: Division of Otolaryngology, Department of Surgery, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada.
authors.forename: Blair A
authors.initials: BA
authors.lastname: Williams
authors.affiliation: Division of Otolaryngology, Department of Surgery, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada.
authors.forename: M Elise R
authors.initials: ME
authors.lastname: Graham
authors.affiliation: Division of Otolaryngology, Department of Surgery, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Rigby
authors.affiliation: Division of Otolaryngology, Department of Surgery, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada.
authors.forename: Jonathan R B
authors.initials: JR
authors.lastname: Trites
authors.affiliation: Division of Otolaryngology, Department of Surgery, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada.
authors.forename: S Mark
authors.initials: SM
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sinal
authors.affiliation: Division of Otolaryngology, Department of Surgery, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada. jim.fawcett@dal.ca.|Department of Pharmacology, Dalhousie University, Halifax, NS, Canada. jim.fawcett@dal.ca.
authors.forename: James P
authors.initials: JP
authors.lastname: Fawcett
authors.affiliation: Division of Otolaryngology, Department of Surgery, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada. drrobhart@gmail.com.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Hart
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D058750:Epithelial-Mesenchymal Transition; D000090683:Hippo Signaling Pathway; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009959:Oropharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D027383:Papillomaviridae; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C488081:NOS1AP protein, human; D010750:Phosphoproteins; C480591:SCRIB protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: HPV; Hippo; NOS1AP; Oropharyngeal squamous cell carcinoma; Scribble; YAP; p16