KCTD4 interacts with CLIC1 to disrupt calcium homeostasis and promote metastasis in esophageal cancer

Increasing evidences suggest the important role of calcium homeostasis in hallmarks of can-cer, 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 pri -mar y 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 dimer-ization, thus increasing intracellular Ca2 thorn 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.

Automated summary

Increasing evidences suggest the important role of calcium homeostasis in cancer, but its function and regulatory network in metastasis remain unclear. This study identifies KCTD4 as a driver of cancer metastasis and finds that high expression of KCTD4 is associated with poor prognosis in patients with esophageal squamous cell carcinoma. KCTD4 enhances cancer cell invasion by increasing fibronectin transcription via NFATc1 and its disruption of CLIC1 dimerization. Furthermore, a lead compound targeting the KCTD4-CLIC1 interaction significantly suppresses cancer metastasis.