Epigenetic dysregulation of K_Ca3.1 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 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 21 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.Lung cancer is a leading cause of cancer-related death. 1 The 5-year survival rate of patients with non-small-cell lung cancer (NSCLC), which accounts for 80% of lung cancers, may be as low as $10%. 2-4 Unfortunately, many patients develop local or distant metastasis relapse even after complete resection. Thus, high aggressiveness is an intrinsic feature of many NSCLC tumors. Adjuvant and palliative chemotherapy are of limited benefit in NSCLC, and novel therapeutic targets are needed.Individual NSCLC cancers harbor multiple mutations in protein-coding genes, most of which cannot be targeted therapeutically. 5 In contrast, epigenetic changes might be targetable. Effector mechanisms, e.g., for metastatic spread, could be promising therapeutic targets. Metastasis development originates from subpopulations of tumor cells that acquire additional features for increased aggressiveness. These features depend on changes in gene expression, including that of ion channels, 6-8 presumably often by epigenetic mechanisms rather than metastasis-specific mutations. 9-11 Altered DNA methylation of specific loci as a stable epigenetic mark is a likely culprit in many instances. DNA hypermethylation and gene silencing occur in CpG islands and promoters of tumor suppressors. 9 DNA hypomethylation is thought to occur mainly in intergenic regions, with effects mainly on genome stability. 9 However, the potential pathophysiological and clinical relevance of DNA hypomethylation of specific

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

“…In humans, overexpression is considered the main mechanism of oncochannels to contribute to the malignancy of cancer (Huber, 2013; Pardo and Stuhmer, 2014), but activating mutations in the SK4‐encoding KCNN4 gene may also contribute to the expression of abnormally regulated channels. Notably, KCNN4 promoter hypomethylation is associated with high levels of SK4 in aggressively growing non‐small‐cell lung carcinoma cell lines and advanced stages of lung cancer in patients (Bulk et al ., 2015). With regard to breast cancer, similar epigenetic changes may account for progression; however, such mechanisms have not been elucidated as of yet.…”

Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway

“…This gene was highly expressed in patients with the cooperative induction of KRT19 and HER2 (data not shown). Of interest, KCNN4 has been reported to be a marker of poor prognosis in NSCLC patients31. Further studies should be performed to understand how the cooperative expression of KRT19 and HER2 contributes to malignant potential of lung cancer.…”

KCNN4andS100A14act as predictors of recurrence in optimally debulked patients with serous ovarian cancer

“…The KCa3.1 channel is an intermediate conductance Ca2+-activated potassium channel that is sensitive to changes in intracellular Ca2+ and is voltage-independent. It had been found to be related to tumor grade, cell proliferation, metastatic spread, and cell cycle progression in several cancer types including prostate, pancreas, and breast cancer [14, 24–27], melanoma [28], endometrial cancer [29], as well as non-small cell lung cancer (NSCLC) [30], but no reports can be seen on SOC. The KCa3.1 channel-specific inhibitor, senicapoc, has been shown to prevent NSCLC proliferation [30].…”