| Summary: | Ewing sarcoma (EwS) is a rare and highly malignant bone tumor occurring mainly in childhood and adolescence. Physiologically, the bone is a central hub for Ca<sup>2+</sup> homeostasis, which is severely disturbed by osteolytic processes in EwS. Therefore, we aimed to investigate how ion transport proteins involved in Ca<sup>2+</sup> homeostasis affect EwS pathophysiology. We characterized the expression of 22 candidate genes of Ca<sup>2+</sup>-permeable or Ca<sup>2+</sup>-regulated ion channels in three EwS cell lines and found the Ca<sup>2+</sup>-activated K<sup>+</sup> channel K<sub>Ca</sub>2.1 (<i>KCNN1</i>) to be exceptionally highly expressed. We revealed that <i>KCNN1</i> expression is directly regulated by the disease-driving oncoprotein EWSR1-FL1. Due to its consistent overexpression in EwS, <i>KCNN1</i> mRNA could be a prognostic marker in EwS. In a large cohort of EwS patients, however, <i>KCNN1</i> mRNA quantity does not correlate with clinical parameters. Several functional studies including patch clamp electrophysiology revealed no evidence for K<sub>Ca</sub>2.1 function in EwS cells. Thus, elevated <i>KCNN1</i> expression is not translated to K<sub>Ca</sub>2.1 channel activity in EwS cells. However, we found that the low K<sup>+</sup> conductance of EwS cells renders them susceptible to hypoosmotic solutions. The absence of a relevant K<sup>+</sup> conductance in EwS thereby provides an opportunity for hypoosmotic therapy that can be exploited during tumor surgery.
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