Epigenetic dysregulation of KCa 3.1 channels induces poor prognosis in lung cancer.
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.
Key words
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