Dupuy Maryne, Gueguinou Maxime, Postec Anaïs, Brion Régis, Tesfaye Robel, Mullard Mathilde, Regnier Laura, Amiaud Jérôme, Hubsch Clémence, Potier-Cartereau Marie, Chantôme Aurélie, Brounais-Le Royer Bénédicte, Baud'huin Marc, Georges Steven, Lamoureux François, Ory Benjamin, Entz-Werlé Natacha, Delattre Olivier, Rédini Françoise, Vandier Christophe, Verrecchia Franck
Nantes Université, INSERM UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France.
N2COx UMR 1069, University of Tours,INSERM, Tours, France.
Oncogene. 2025 Jan;44(2):79-91. doi: 10.1038/s41388-024-03199-7. Epub 2024 Nov 1.
Ewing sarcoma (ES) is characterized by EWS::FLI1 or EWS::ERG fusion proteins. Knowing that ion channels are involved in tumorigenesis, this work aimed to study the involvement of the KCNN1 gene, which encodes the SK1 potassium channel, in ES development. Bioinformatics analyses from databases were used to study KCNN1 expression in patients and cell lines. Molecular approaches and in vitro assays were used to study the transcriptional regulation of KCNN1 and its involvement in the regulation of ES cell proliferation. KCNN1 is overexpressed in ES patient biopsies, and its expression is inversely correlated with patient survival. EWS::FLI1, like EWS::ERG, promotes KCNN1 and SK1 expression, binding to GGAA microsatellites near the promoter of KCNN1 isoforms. KCNN1 is involved in the regulation of ES cell proliferation, with its silencing being associated with a slowing of the cell cycle, and its expression modulates membrane potential and therefore calcium flux. These results highlight that KCNN1 is a direct target of EWS::FLI1 and EWS::ERG and demonstrate that KCNN1 is involved in the regulation of intracellular calcium activity and ES cell proliferation, making it a promising therapeutic target in ES.
尤因肉瘤（ES）的特征在于EWS::FLI1或EWS::ERG融合蛋白。鉴于离子通道参与肿瘤发生，本研究旨在探讨编码SK1钾通道的KCNN1基因在ES发展中的作用。利用数据库的生物信息学分析来研究KCNN1在患者和细胞系中的表达。采用分子方法和体外试验来研究KCNN1的转录调控及其在ES细胞增殖调控中的作用。KCNN1在ES患者活检组织中过表达，其表达与患者生存率呈负相关。EWS::FLI1与EWS::ERG一样，促进KCNN1和SK1的表达，与KCNN1亚型启动子附近的GGAA微卫星结合。KCNN1参与ES细胞增殖的调控，其沉默与细胞周期减慢有关，其表达调节膜电位，进而调节钙通量。这些结果表明，KCNN1是EWS::FLI1和EWS::ERG的直接靶点，并证明KCNN1参与细胞内钙活性和ES细胞增殖的调控，使其成为ES中有前景的治疗靶点。
