We postulated that there might be a correlation between EZH2 and the expression TSSC3. In this study, we demonstrate for the first time in osteosarcoma that EZH2 knockdown inhibits cell proliferation, migration and invasion in vitro, and growth of tumor xenografts and lung metastasis in vivo by facilitating the re-expression of TSSC3, activating the corresponding apoptosis pathway. This evidence concerns the gene PHLDA2 and neoplasm.