title: Epigenetic dysregulation of KCa 3.1 channels induces poor prognosis in lung cancer.
abstract: Epigenomic changes are an important feature of malignant tumors. How tumor aggressiveness is affected by DNA methylation of specific loci is largely unexplored. In genome-wide DNA methylation analyses, we identified the KCa 3.1 channel gene (KCNN4) promoter to be hypomethylated in an aggressive non-small-cell lung carcinoma (NSCLC) cell line and in patient samples. Accordingly, KCa 3.1 expression was increased in more aggressive NSCLC cells. Both findings were strong predictors for poor prognosis in lung adenocarcinoma. Increased KCa 3.1 expression was associated with aggressive features of NSCLC cells. Proliferation and migration of pro-metastatic NSCLC cells depended on KCa 3.1 activity. Mechanistically, elevated KCa 3.1 expression hyperpolarized the membrane potential, thereby augmenting the driving force for Ca(2+) influx. KCa 3.1 blockade strongly reduced the growth of xenografted NSCLC cells in mice as measured by positron emission tomography-computed tomography. Thus, loss of DNA methylation of the KCNN4 promoter and increased KCa 3.1 channel expression and function are mechanistically linked to poor survival of NSCLC patients.
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany.
authors.forename: Etmar
authors.initials: E
authors.lastname: Bulk
authors.affiliation: Laboratory of Cellular Physiology, EA 4667, SFR CAP-SANTE (FED4231), UFR Sciences, University of Picardie Jules Verne, Amiens, 80039, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Ay
authors.affiliation: Laboratory of Cellular Physiology, EA 4667, SFR CAP-SANTE (FED4231), UFR Sciences, University of Picardie Jules Verne, Amiens, 80039, France.|Inserm U916, Institut Bergonié, Bordeaux, 33076, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Hammadi
authors.affiliation: Laboratory of Cellular Physiology, EA 4667, SFR CAP-SANTE (FED4231), UFR Sciences, University of Picardie Jules Verne, Amiens, 80039, France.
authors.forename: Halima
authors.initials: H
authors.lastname: Ouadid-Ahidouch
authors.affiliation: European Institute for Molecular Imaging (EIMI), University of Münster, Münster, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schelhaas
authors.affiliation: Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Hascher
authors.affiliation: Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.|Department of Medicine, Hematology and Oncology, University Hospital of Halle (Saale), Halle (Saale), Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rohde
authors.affiliation: Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.|Department of Internal Medicine II and Clinic (Oncology Center), University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nils H
authors.initials: NH
authors.lastname: Thoennissen
authors.affiliation: Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Wiewrodt
authors.affiliation: Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Department of Thoracic Surgery, Niels-Stensen Clinics, Ostercappeln, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marra
authors.affiliation: Department of Thoracic Surgery, Niels-Stensen Clinics, Ostercappeln, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Hillejan
authors.affiliation: European Institute for Molecular Imaging (EIMI), University of Münster, Münster, Germany.|Department of Geriatric Medicine, Johanniter Hospital, Bonn, Germany.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Jacobs
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.affiliation: Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.|Department of Medicine, Hematology and Oncology, University Hospital of Halle (Saale), Halle (Saale), Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Schwab
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D005260:Female; D064593:Heterografts; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human
keywords: KCa3.1; aggressiveness; lung cancer