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Epigenetic dysregulation of KCa 3.1 channels induces poor prognosis in lung cancer.
Bulk, Etmar; Ay, Anne-Sophie; Hammadi, Mehdi; Ouadid-Ahidouch, Halima; Schelhaas, Sonja; Hascher, Antje; Rohde, Christian; Thoennissen, Nils H; Wiewrodt, Rainer; Schmidt, Eva; Marra, Alessandro; Hillejan, Ludger; Jacobs, Andreas H; Klein, Hans-Ulrich; Dugas, Martin; Berdel, Wolfgang E; Müller-Tidow, Carsten; Schwab, Albrecht.
Affiliation
  • Bulk E; Institute of Physiology II, University of Münster, Münster, Germany.
  • Ay AS; Laboratory of Cellular Physiology, EA 4667, SFR CAP-SANTE (FED4231), UFR Sciences, University of Picardie Jules Verne, Amiens, 80039, France.
  • Hammadi M; Laboratory of Cellular Physiology, EA 4667, SFR CAP-SANTE (FED4231), UFR Sciences, University of Picardie Jules Verne, Amiens, 80039, France.
  • Ouadid-Ahidouch H; Inserm U916, Institut Bergonié, Bordeaux, 33076, France.
  • Schelhaas S; Laboratory of Cellular Physiology, EA 4667, SFR CAP-SANTE (FED4231), UFR Sciences, University of Picardie Jules Verne, Amiens, 80039, France.
  • Hascher A; European Institute for Molecular Imaging (EIMI), University of Münster, Münster, Germany.
  • Rohde C; Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
  • Thoennissen NH; Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
  • Wiewrodt R; Department of Medicine, Hematology and Oncology, University Hospital of Halle (Saale), Halle (Saale), Germany.
  • Schmidt E; Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
  • Marra A; Department of Internal Medicine II and Clinic (Oncology Center), University Hospital Hamburg-Eppendorf, Hamburg, Germany.
  • Hillejan L; Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
  • Jacobs AH; Department of Medicine, Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
  • Klein HU; Department of Thoracic Surgery, Niels-Stensen Clinics, Ostercappeln, Germany.
  • Dugas M; Department of Thoracic Surgery, Niels-Stensen Clinics, Ostercappeln, Germany.
  • Berdel WE; European Institute for Molecular Imaging (EIMI), University of Münster, Münster, Germany.
  • Müller-Tidow C; Department of Geriatric Medicine, Johanniter Hospital, Bonn, Germany.
  • Schwab A; Institute of Medical Informatics, University of Münster, Münster, Germany.
Int J Cancer ; 137(6): 1306-17, 2015 Sep 15.
Article in En | MEDLINE | ID: mdl-25704182
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.
Subject(s)
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Epigenesis, Genetic / Intermediate-Conductance Calcium-Activated Potassium Channels / Lung Neoplasms Type of study: Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Int J Cancer Year: 2015 Document type: Article Affiliation country: Germany Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Epigenesis, Genetic / Intermediate-Conductance Calcium-Activated Potassium Channels / Lung Neoplasms Type of study: Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Int J Cancer Year: 2015 Document type: Article Affiliation country: Germany Country of publication: United States