Chimeric protein EWS::FLI1 drives cell proliferation in Ewing Sarcoma via aberrant expression of KCNN1/SK1 and dysregulation of calcium signaling.

IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Oncogene Pub Date : 2024-11-01 DOI:10.1038/s41388-024-03199-7
Maryne Dupuy, Maxime Gueguinou, Anaïs Postec, Régis Brion, Robel Tesfaye, Mathilde Mullard, Laura Regnier, Jérôme Amiaud, Clémence Hubsch, Marie Potier-Cartereau, Aurélie Chantôme, Bénédicte Brounais-Le Royer, Marc Baud'huin, Steven Georges, François Lamoureux, Benjamin Ory, Natacha Entz-Werlé, Olivier Delattre, Françoise Rédini, Christophe Vandier, Franck Verrecchia
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引用次数: 0

Abstract

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.

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嵌合蛋白 EWS::FLI1 通过 KCNN1/SK1 的异常表达和钙信号转导失调驱动尤文肉瘤细胞增殖。
尤文肉瘤(ES)的特征是EWS::FLI1或EWS::ERG融合蛋白。鉴于离子通道参与肿瘤发生,这项工作旨在研究编码 SK1 钾通道的 KCNN1 基因参与 ES 发育的情况。我们利用数据库中的生物信息学分析来研究 KCNN1 在患者和细胞系中的表达。利用分子方法和体外试验研究了 KCNN1 的转录调控及其参与 ES 细胞增殖调控的情况。KCNN1在ES患者活检组织中过度表达,其表达与患者存活率成反比。EWS::FLI1与EWS::ERG一样,能促进KCNN1和SK1的表达,与KCNN1同工酶启动子附近的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,其表达可调节膜电位,从而调节钙通量。这些结果突出表明,KCNN1是EWS::FLI1和EWS::ERG的直接靶标,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的一个有希望的治疗靶标。
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来源期刊
Oncogene
Oncogene 医学-生化与分子生物学
CiteScore
15.30
自引率
1.20%
发文量
404
审稿时长
1 months
期刊介绍: Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.
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