Chimeric protein EWS-FLI1 drives cell proliferation in Ewing Sarcomaviaoverexpression ofKCNN1

Abstract

AbstractEwing sarcoma (ES) is characterized by chimeric fusion proteins, which act as oncogenes. Over the last decade, patient survival has not increased, especially for high risk patients. Knowing that ion channels are studied for their implication in tumorigenesis, the aim of this work is to study the involvement of the SK1 potassium channels in ES. RNA-Seq analyses showed a high restricted expression ofKCNN1, the gene encoding SK1, only in ES patients, and its expression is inversely correlated with patient survival. EWS-FLI1 silencing demonstrated the regulation ofKCNN1by these fusion proteins, which bind at GGAA microsatellites nearKCNN1promoter. In addition,KCNN1has been shown to be involved in the regulation of ES cell proliferation, its silencing being associated with a slowing of the cell cycle. Finally,KCNN1expression modulates membrane potential and calcium flux suggesting the role of calcium inKCNN1driving cell proliferation. These results highlight thatKCNN1is a direct EWS-FLI1 and EWS-ERG target, and is involved in the regulation of ES cell proliferation, making it an interesting therapeutic target in ES.