Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models. Mechanistically, CLIC1 enriches to the plasma membrane during mitosis and cooperates with potassium channel EAG2 at lipid rafts to regulate cell volume homeostasis. CLIC1 deficiency is associated with elevation of cell/nuclear volume ratio, uncoupling between RNA biosynthesis and cell size increase, and activation of the p38 MAPK pathway that suppresses proliferation. Concurrent knockdown of CLIC1/EAG2 and their evolutionarily conserved channels synergistically suppressed the growth of human medulloblastoma cells and Drosophila melanogaster brain tumors, respectively. These findings establish CLIC1 as a molecular dependency in rapidly dividing medulloblastoma cells, provide insights into the mechanism by which CLIC1 regulates tumorigenesis, and reveal that targeting CLIC1 and its functionally cooperative potassium channel is a disease-intervention strategy.

中文翻译：

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氯离子细胞内通道1与钾通道EAG2协同促进髓母细胞瘤生长

离子通道代表一大类药物靶点，但它们在脑癌中的作用尚未得到充分研究。在这里，我们发现氯细胞内通道 1 (CLIC1) 在人类中枢神经系统恶性肿瘤中过度表达，包括髓母细胞瘤（一种常见的儿科脑癌）。虽然整体敲除不会明显影响小鼠的发育，但 CLIC1 的基因缺失会抑制异种移植和基因工程小鼠模型中髓母细胞瘤的生长。从机制上讲，CLIC1 在有丝分裂过程中富集到质膜上，并与脂筏上的钾通道 EAG2 配合调节细胞体积稳态。CLIC1 缺陷与细胞/核体积比的升高、RNA 生物合成和细胞大小增加之间的解偶联以及抑制增殖的 p38 MAPK 途径的激活有关。同时敲低 CLIC1/EAG2 及其进化上保守的通道分别协同抑制人髓母细胞瘤细胞和果蝇脑肿瘤的生长。这些发现确立了 CLIC1 作为快速分裂的髓母细胞瘤细胞的分子依赖性，提供了对 CLIC1 调节肿瘤发生的机制的见解，并揭示了针对 CLIC1 及其功能协同钾通道是一种疾病干预策略。