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Epigenetic dysregulation of K Ca 3.1 channels induces poor prognosis in lung cancer
Author(s) -
Bulk Etmar,
Ay AnneSophie,
Hammadi Mehdi,
OuadidAhidouch Halima,
Schelhaas Sonja,
Hascher Antje,
Rohde Christian,
Thoennissen Nils H.,
Wiewrodt Rainer,
Schmidt Eva,
Marra Alessandro,
Hillejan Ludger,
Jacobs Andreas H.,
Klein HansUlrich,
Dugas Martin,
Berdel Wolfgang E.,
MüllerTidow Carsten,
Schwab Albrecht
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29490
Subject(s) - dna methylation , cancer research , lung cancer , epigenetics , epigenomics , methylation , adenocarcinoma , carcinoma , medicine , oncology , biology , cancer , gene expression , gene , genetics
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 K Ca 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, K Ca 3.1 expression was increased in more aggressive NSCLC cells. Both findings were strong predictors for poor prognosis in lung adenocarcinoma. Increased K Ca 3.1 expression was associated with aggressive features of NSCLC cells. Proliferation and migration of pro‐metastatic NSCLC cells depended on K Ca 3.1 activity. Mechanistically, elevated K Ca 3.1 expression hyperpolarized the membrane potential, thereby augmenting the driving force for Ca 2+ influx. K Ca 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 K Ca 3.1 channel expression and function are mechanistically linked to poor survival of NSCLC patients.