越来越多的证据表明钙稳态在癌症特征中发挥重要作用，但其在转移中的功能和调节网络仍不清楚。迫切需要对癌症转移的关键调节因子进行全面研究。原发性食管鳞状细胞癌 (ESCC) 和匹配的转移组织的转录组测序 (RNA-seq) 以及一系列功能获得/丧失实验确定含钾通道四聚化结构域 4 (KCTD4) 是癌症转移的驱动因素。发现 KCTD4 表达在转移性 ESCC 中上调。 KCTD4 高表达与 ESCC 患者预后不良相关，并导致癌症体外和体内转移。从机制上讲，KCTD4 与 CLIC1 结合并破坏其二聚化，从而增加细胞内 Ca2+ 水平，从而增强 NFATc1 依赖性纤连蛋白转录。 KCTD4诱导的纤连蛋白分泌以旁分泌方式激活成纤维细胞，进而通过MMP24信号传导作为正反馈促进癌细胞侵袭。此外，先导化合物 K279-0738 通过靶向 KCTD4-CLIC1 相互作用显着抑制癌症转移，提供了一种潜在的治疗策略。总而言之，我们的研究不仅揭示了 KCTD4 作为钙稳态调节剂，而且还揭示了 KCTD4/CLIC1-Ca2 -NFATc1-纤连蛋白信号传导作为癌症转移的新机制。这些发现验证了 KCTD4 作为 ESCC 的潜在预后生物标志物和治疗靶点。© 2023 中国药学会和中国医学科学院药物研究所。由 Elsevier B.V. 制作和主持

Increasing evidences suggest the important role of calcium homeostasis in hallmarks of cancer, but its function and regulatory network in metastasis remain unclear. A comprehensive investigation of key regulators in cancer metastasis is urgently needed. Transcriptome sequencing (RNA-seq) of primary esophageal squamous cell carcinoma (ESCC) and matched metastatic tissues and a series of gain/loss-of-function experiments identified potassium channel tetramerization domain containing 4 (KCTD4) as a driver of cancer metastasis. KCTD4 expression was found upregulated in metastatic ESCC. High KCTD4 expression is associated with poor prognosis in patients with ESCC and contributes to cancer metastasis in vitro and in vivo. Mechanistically, KCTD4 binds to CLIC1 and disrupts its dimerization, thus increasing intracellular Ca2+ level to enhance NFATc1-dependent fibronectin transcription. KCTD4-induced fibronectin secretion activates fibroblasts in a paracrine manner, which in turn promotes cancer cell invasion via MMP24 signaling as positive feedback. Furthermore, a lead compound K279-0738 significantly suppresses cancer metastasis by targeting the KCTD4‒CLIC1 interaction, providing a potential therapeutic strategy. Taken together, our study not only uncovers KCTD4 as a regulator of calcium homeostasis, but also reveals KCTD4/CLIC1-Ca2+-NFATc1-fibronectin signaling as a novel mechanism of cancer metastasis. These findings validate KCTD4 as a potential prognostic biomarker and therapeutic target for ESCC.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.