The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma

Authors

Faisal Alzahrani, QEII Health Sciences Centre
Leanne Clattenburg, Dalhousie University, Faculty of Medicine
Shanmugam Muruganandan, Dalhousie University, Faculty of Medicine
Martin Bullock, QEII Health Sciences Centre
Kaitlyn MacIsaac, Dalhousie University, Faculty of Medicine
Michael Wigerius, Dalhousie University, Faculty of Medicine
Blair A. Williams, QEII Health Sciences Centre
M. Elise R. Graham, QEII Health Sciences CentreFollow
Matthew H. Rigby, QEII Health Sciences Centre
Jonathan R.B. Trites, QEII Health Sciences Centre
S. Mark Taylor, QEII Health Sciences Centre
Christopher J. Sinal, Dalhousie University, Faculty of Medicine
James P. Fawcett, QEII Health Sciences Centre
Robert D. Hart, QEII Health Sciences Centre

Document Type

Article

Publication Date

2-22-2017

Journal

Journal of Otolaryngology - Head and Neck Surgery

Volume

46

Issue

1

URL with Digital Object Identifier

10.1186/s40463-017-0187-1

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 CO2 laser 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. Conclusion: 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.