TOX3 inhibits cancer cell migration and invasion via transcriptional regulation of SNAI1 and SNAI2 in clear cell renal cell carcinoma

Studies on the mechanism of clear cell renal cell carcinoma (ccRCC) progression are lacking. In this study, TOX3 was identified as a novel cancer suppressor gene in ccRCC. Hypermethylation of CpG probes in the promoter region was associated with the functional loss of TOX3 in ccRCC cancer tissues. Downregulation of TOX3 mRNA was strongly associated with poor clinical outcomes in ccRCC. Immunohistochemistry confirmed TOX3 was downregulated in primary tumors without metastasis (n = 126) and further downregulated in primary metastatic tumors (n = 23) compared with adjacent noncancerous tissues (n = 92). In vitro, overexpression of TOX3 inhibited RCC cell growth, migration and invasion. Mechanistic investigations showed that TOX3 deficiency facilitates the epithelial-mesenchymal transition due to impairment of transcriptional repression of SNAIL members SNAI1 and SNAI2 and promotes cancer cell migration and invasion. In vivo, restoring TOX3 expression reduced lung metastatic lesions and prolonged survival of mice. TOX3 combined with SNAIl or SNAI2 predicted overall survival in ccRCC patients. Blockage of this pathway could be a promising therapeutic target for advanced ccRCC.