title: TMEM16A/ANO1 is differentially expressed in HPV-negative versus HPV-positive head and neck squamous cell carcinoma through promoter methylation.
abstract: Head and neck squamous cell carcinoma (HNSCC) has a variety of causes. Recently, the human papilloma virus (HPV) has been implicated in the rising incidence of oropharyngeal cancer and has led to variety of studies exploring the differences between HPV-positive and HPV-negative HNSCC. The calcium-activated chloride channel TMEM16A is overexpressed in a variety of cancers, including HNSCC, but whether or not it plays different roles in HPV-positive and HPV-negative HNSCC is unknown. Here, we demonstrate that TMEM16A is preferentially overexpressed in HPV-negative HNSCC and that this overexpression of TMEM16A is associated with decreased patient survival. We also show that TMEM16A expression is decreased in HPV-positive HNSCC at the DNA, RNA, and protein levels in patient samples as well as cell lines. We demonstrate that the lower levels of TMEM16A expression in HPV-positive tumors can be attributed to both a combination of copy number alteration and promoter methylation at the DNA level. Additionally, our cellular data show that HPV-negative cell lines are more dependent on TMEM16A for survival than HPV-positive cell lines. Therefore, we suspect that the down-regulation of TMEM16A in HPV-positive HNSCC makes TMEM16A a poor therapeutic target in HPV-positive HNSCC, but a potentially useful target in HPV-negative HNSCC.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania USA.
authors.forename: Ronak
authors.initials: R
authors.lastname: Dixit
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Kemp
authors.affiliation: VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kulich
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania USA.
authors.forename: Raja
authors.initials: R
authors.lastname: Seethala
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania USA.
authors.forename: Simion
authors.initials: S
authors.lastname: Chiosea
authors.affiliation: Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland USA.
authors.forename: Shizhang
authors.initials: S
authors.lastname: Ling
authors.affiliation: Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland USA.
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Ha
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania USA.|VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania USA.
authors.forename: Umamaheswar
authors.initials: U
authors.lastname: Duvvuri
mesh_terms: D000075369:Anoctamin-1; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D027383:Papillomaviridae / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D034622:RNA Interference; D016019:Survival Analysis
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D018118:Chloride Channels; D009363:Neoplasm Proteins