title: Frequent aberrant expression of the human ether à go-go (hEAG1) potassium channel in head and neck cancer: pathobiological mechanisms and clinical implications.
abstract: Compelling evidence indicates that the human ether-à-go-go voltage-gated potassium channels (hEAG1) may represent new valuable membrane therapeutic targets and diagnostic/prognostic biomarkers in various cancers. This study is the first to investigate the expression of hEAG1 potassium channel subunit in both primary tumors and HNSCC-derived cell lines to ascertain its clinical and biological role in tumor progression. Our findings demonstrate that hEAG1 is frequently aberrantly expressed in a high percentage of primary tumors (83 %, 45/54 cases) and HNSCC-derived cell lines (83 %, 10/12 cell lines). hEAG1 expression increased during HNSCC progression and was more frequent in advanced tumors. Strikingly, hEAG1 expression was also detected in a notable proportion (39 %, 17/44 cases) of patient-matched normal adjacent mucosa, whereas no expression was detected in normal epithelia from non-oncologic patients without exposure to tobacco carcinogens. In an attempt to identify the underlying mechanisms of aberrant hEAG1 expression in HNSCC, we found that hEAG1 gene copy gain occurred at a low frequency (15 %, 13/88 cases) in primary tumors but was not observed in early stages of HNSCC tumorigenesis. Furthermore, this study provides original evidence supporting the involvement of histone acetylation (i.e., H3Ac and H4K16Ac activating marks) in the regulation of hEAG1 expression in HNSCC. In addition, functional studies in HNSCC cells further revealed that hEAG1 expression is a biologically relevant feature that promotes cell proliferation and invasion, although independently of its ion-conducting function. Our findings strongly support the notion that hEAG1 may represent a promising candidate as tumor marker and membrane therapeutic target for HNSCC treatment.
authors.affiliation: Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain.
authors.forename: Sofía Tirados
authors.initials: ST
authors.lastname: Menéndez
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Villaronga
authors.forename: Juan P
authors.initials: JP
authors.lastname: Rodrigo
authors.forename: Saúl
authors.initials: S
authors.lastname: Alvarez-Teijeiro
authors.forename: Darío
authors.initials: D
authors.lastname: García-Carracedo
authors.forename: Rocío G
authors.initials: RG
authors.lastname: Urdinguio
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pardo
authors.forename: Cristina Gutiérrez
authors.initials: CG
authors.lastname: Viloria
authors.forename: Carlos
authors.initials: C
authors.lastname: Suárez
authors.forename: Juana María
authors.initials: JM
authors.lastname: García-Pedrero
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D044127:Epigenesis, Genetic; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007822:Laryngeal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010610:Pharyngeal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016016:Proportional Hazards Models; D017422:Sequence Analysis, DNA
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human