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

作　　者：Cancan Zheng Xiaomei Yu Taoyang Xu Zhichao Liu Zhili Jiang Jiaojiao Xu Jing Yang Guogeng Zhang Yan He Han Yang Xingyuan Shi Zhigang Li Jinbao Liu Wen Wen Xu 

机构地区：[1]Key Laboratory of Biological Targeting Diagnosis,Therapy and Rehabilitation of Guangdong Higher Education Institutes,the Fifth Affiliated Hospital of Guangzhou Medical University,Guangzhou 510230,China [2]Department of Thoracic Surgery,Shanghai Chest Hospital,School of Medicine,Shanghai Jiao Tong University.Shanghai 200030,China [3]Department of Radiation Oncology,the Fifth Affiliated Hospital of Guangzhou Medical University,Guangzhou 510230,China [4]Department of Thoracic Surgery,Sun Yat-sen University Cancer Center,Guangzhou 510060,China [5]Guangdong Provincial Key Laboratory of Protein Modification and Degradation,State Key Laboratory of Respiratory Disease,and School of Basic Medical Sciences,Guangzhou Medical University,Guangzhou 511495,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第10期4217-4233,共17页药学学报（英文版）

基　　金：supported by National Natural Science Foundation of China(82273368,82073196,82204455);the National Key Research and Development Program of China(2021YFC2501900);Natural Science foundation of Guangdong Province(2021A1515011158,2021A0505030035,China);Guangdong Basic and Applied Basic Research Foundation Outstanding Youth Project(2023B1515020012,China);Guangzhou Science and Technology Project(202201020032,China);Key Laboratory of Guangdong Higher Education Institutes(2021KSY009,China);Open Project funded by the MOE Key Laboratory of Tumor Molecular Biology(2023 Open Project-50411651-2020-1,China)。

摘　　要：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 Ca^(2+)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-Ca^(2+)-NFATc1-fibronectin signaling as a novel mechanism of cancer metastasis.These findings validate KCTD4 as a potential prognostic biomarker and therapeutic target for ESCC.

关 键 词：Cancermetastasis Calcium homeostasis NFAT signaling FIBROBLASTS Esophageal cancer 

分 类 号：R735.1[医药卫生—肿瘤]