Epigenetic dysregulation of KCa3.1 channels induces poor prognosis in lung cancer

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 Ca2+ 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. What's New? Another possible avenue for thwarting metastasis has been found: the potassium channel K(Ca)3.1. Aggressiveness in lung cancer (NSCLC) is linked to methylation of the potassium channel promoter gene. When the promoter is under-methylated, more of the potassium channel protein is produced, and the cancer cells proliferate and spread more aggressively. The authors also showed that blocking K(Ca)3.1 stops the cells from dividing and spreading, both in vitro and in mice, suggesting that K(Ca)3.1 could make a promising therapeutic target.