SOX10, a novel HMG-box-containing tumor suppressor, inhibits growth and metastasis of digestive cancers by suppressing the Wnt/β-catenin pathway

// Xin Tong 1,2,3 , Lili Li 4 , Xiaoyan Li 1,2 , Lei Heng 1 , Lan Zhong 4 , Xianwei Su 4 , Rong Rong 4 , Shi Hu 1 , Wenjia Liu 2 , Baoqing Jia 2 , Xing Liu 5 , Geng Kou 1,3 , Jun Han 3,6 , Shangjing Guo 3 , Yi Hu 2 , Cheng Li 2 , Qian Tao 4 and Yajun Guo 1,2,3,6 1 International Joint Cancer Institute, The Second Military Medical University, Shanghai, China 2 PLA General Hospital Cancer Center Key Laboratory, Medical School of Chinese PLA, Beijing, China 3 Department of Pharmacy, Liao Cheng University, Shandong, China 4 Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 5 150 hospital of Chinese PLA, Luoyang, China 6 State Key Laboratory of Antibody Medicine & Targeting Therapy and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, China Correspondence: Yajun Guo, email: // Qian Tao, email: // Keywords : SOX10, tumor suppressor gene, digestive cancer, methylation, β-catenin signaling Received : July 12, 2014 Accepted : September 24, 2014 Published : September 25, 2014 Abstract SOX10 was identified as a methylated gene in our previous cancer methylome study. Here we further analyzed its epigenetic inactivation, biological functions and related cell signaling in digestive cancers (colorectal, gastric and esophageal cancers) in detail. SOX10 expression was decreased in multiple digestive cancer cell lines as well as primary tumors due to its promoter methylation. Pharmacologic or genetic demethylation reversed SOX10 silencing. Ectopic expression of SOX10in SOX10 -deficient cancer cells inhibits their proliferation, tumorigenicity, and metastatic potentials in vitro and in vivo . SOX10 also suppressed the epithelial to mesenchymal transition (EMT) and stemness properties of digestive tumor cells. Mechanistically, SOX10 competes with TCF4 to bind β-catenin and transrepresses its downstream target genes via its own DNA-binding property. SOX10 mutations that disrupt the SOX10-β-catenin interaction partially prevented tumor suppression. SOX10is thus a commonly inactivated tumor suppressor that antagonizes Wnt/β-catenin signaling in cancer cells from different digestive tissues.