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Frequent aberrant expression of the human ether à go-go (hEAG1) potassium channel in head and neck cancer: pathobiological mechanisms and clinical implications

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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.

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Acknowledgements

We are grateful to all members of the Cancer Epigenetic Unit (IUOPA, Oviedo, Spain) and the Department of Molecular Biology of Neuronal Signals (Max-Planck-Institute, Göttingen, Germany), and Dr. Marta Alonso, Dr. Angel M. Nistal, Dr. José Luís Martínez and Ana Salas (SCT Facilities, University of Oviedo) for excellent technical assistance. We also thank Pablo Martínez-Camblor (OIB-CAIBER) for his assistance with statistical analyses, and Teresa Ortega and OIB staff for their administrative support. This work was supported by grants from Fondo de Investigación Sanitaria CP07/00032 and PI10/00157 (to J.M.G.P), PI11/00929 (to C.S.), ISCIII Fondos FEDER, RTICC (RD06/0020/0034) and Obra Social Cajastur-IUOPA. S.T.M. and S.A.T. are recipients of a fellowship from FICYT (BP08-007 and BP11-114).

Disclosure statement

L.A.P. is shareholder at iOnGen AG.

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Authors and Affiliations

  1. Servicio de Otorrinolaringología, Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain

    Sofía Tirados Menéndez, María Ángeles Villaronga, Juan P. Rodrigo, Saúl Álvarez-Teijeiro, Darío García-Carracedo, Cristina Gutiérrez Viloria, Carlos Suárez & Juana María García-Pedrero

  2. Unidad de Epigenética del Cáncer, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain

    Rocío G. Urdinguio & Mario F. Fraga

  3. Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, Madrid, 28049, Spain

    Mario F. Fraga

  4. Department of Molecular Biology of Neuronal Signals, Max-Planck-Institute of Experimental Medicine, Göttingen, Germany

    Luis A. Pardo

  5. Hospital Universitario Central de Asturias, Laboratorio 2 ORL—IUOPA, 33006, Oviedo, Spain

    Juana María García-Pedrero

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  1. Sofía Tirados Menéndez
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  2. María Ángeles Villaronga
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  9. Cristina Gutiérrez Viloria
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  10. Carlos Suárez
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  11. Juana María García-Pedrero
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Correspondence to Juana María García-Pedrero.

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Menéndez, S.T., Villaronga, M.Á., Rodrigo, J.P. et al. Frequent aberrant expression of the human ether à go-go (hEAG1) potassium channel in head and neck cancer: pathobiological mechanisms and clinical implications. J Mol Med 90, 1173–1184 (2012). https://doi.org/10.1007/s00109-012-0893-0

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  • DOI: https://doi.org/10.1007/s00109-012-0893-0

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