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
Institute of Physiology II, University of Münster, Münster, Germany.
Laboratory of Cellular Physiology, EA 4667, SFR CAP-SANTE (FED4231), UFR Sciences, University of Picardie Jules Verne, Amiens, 80039, France.
Int J Cancer. 2015 Sep 15;137(6):1306-17. doi: 10.1002/ijc.29490. Epub 2015 May 29.
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.
表观基因组变化是恶性肿瘤的一个重要特征。特定基因座的DNA甲基化如何影响肿瘤侵袭性在很大程度上尚未得到探索。在全基因组DNA甲基化分析中，我们发现钾钙激活通道蛋白3.1（KCa 3.1）通道基因（KCNN4）启动子在一种侵袭性非小细胞肺癌（NSCLC）细胞系和患者样本中存在低甲基化。相应地，在侵袭性更强的NSCLC细胞中KCa 3.1表达增加。这两个发现都是肺腺癌预后不良的有力预测指标。KCa 3.1表达增加与NSCLC细胞的侵袭性特征相关。促转移NSCLC细胞的增殖和迁移依赖于KCa 3.1活性。从机制上讲，KCa 3.1表达升高使膜电位超极化，从而增强了钙离子内流的驱动力。通过正电子发射断层扫描-计算机断层扫描测量，KCa 3.1阻断显著降低了小鼠体内异种移植NSCLC细胞的生长。因此，KCNN4启动子的DNA甲基化缺失以及KCa 3.1通道表达和功能增加在机制上与NSCLC患者的不良生存相关。
