Chimeric protein EWS-FLI1 drives cell proliferation in Ewing Sarcoma via overexpression of KCNN1.

Dupuy, M.; Gueguinou, M.; Postec, A.; Brion, R.; Tesfaye, R.; Mullard, M.; Regnier, L.; Amiaud, J.; Potier-Cartereau, M.; Chantome, A.; Brounais-Le Royer, B.; Baud'huin, M.; Georges, S.; Lamoureux, F.; Ory, B.; Delattre, O.; Redini, F.; Vandier, C.; Verrecchia, F.

doi:10.1101/2023.04.24.538050

bioRxiv · 10.1101/2023.04.24.538050

Chimeric protein EWS-FLI1 drives cell proliferation in Ewing Sarcoma via overexpression of KCNN1.

Dupuy, M.·Gueguinou, M.·Postec, A.·Brion, R.·Tesfaye, R.·Mullard, M.·Regnier, L.·Amiaud, J.·Potier-Cartereau, M.·Chantome, A.·Brounais-Le Royer, B.·Baud'huin, M.·Georges, S.·Lamoureux, F.·Ory, B.·Delattre, O.·Redini, F.·Vandier, C.·Verrecchia, F.

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Abstract

Ewing 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 of KCNN1, the gene encoding SK1, only in ES patients, and its expression is inversely correlated with patient survival. EWS-FLI1 silencing demonstrated the regulation of KCNN1 by these fusion proteins, which bind at GGAA microsatellites near KCNN1 promoter. In addition, KCNN1 has been shown to be involved in the regulation of ES cell proliferation, its silencing being associated with a slowing of the cell cycle. Finally, KCNN1 expression modulates membrane potential and calcium flux suggesting the role of calcium in KCNN1 driving cell proliferation. These results highlight that KCNN1 is 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.

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Dupuy, M., Gueguinou, M., Postec, A., Brion, R., Tesfaye, R., Mullard, M., Regnier, L., Amiaud, J., Potier-Cartereau, M., Chantome, A., Brounais-Le Royer, B., Baud'huin, M., Georges, S., Lamoureux, F., Ory, B., Delattre, O., Redini, F., Vandier, C., Verrecchia, F.. 2023-04-28. Chimeric protein EWS-FLI1 drives cell proliferation in Ewing Sarcoma via overexpression of KCNN1.. https://doi.org/10.1101/2023.04.24.538050

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