越来越多的证据表明钙稳态在癌症标志中的重要作用，但其在转移中的功能和调控网络仍不清楚。迫切需要对癌症转移中的关键调节因子进行全面调查。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）和一系列功能获得/丧失实验确定含有钾通道四聚化结构域4（KCTD4）是癌症转移的驱动因素。在转移性ESCC中发现KCTD4表达上调。高KCTD4表达与ESCC患者的不良预后相关，并有助于体内外癌症转移。机械上,KCTD4与CLIC1结合并破坏其二聚化，从而增加细胞内Ca2+水平以增强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，这反过来促进癌细胞侵袭通过MMP24信号作为正反馈。此外，先导化合物K279-0738通过靶向KCTD4-CLIC1相互作用显著抑制癌症转移，提供潜在的治疗策略。一起来看,我们的研究不仅揭示了KCTD4作为钙稳态的调节剂，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标。
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.
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