The polycomb group protein enhancer of zeste homologue 2 (EZH2), which has histone methyltransferase (HMT) activity, is overexpressed in malignant tumours. However, the role ofEZH2in colorectal cancer (CRC) invasion is little known. Here we investigated the clinical significance, biological effects, and mechanisms ofEZH2signalling. Knockdown ofEZH2significantly reduced cell invasion and secretion of matrix metalloproteinases 2/9 (MMP2/9) inin vitrostudies. Knockdown ofEZH2dramatically increased overall survival and decreased metastasis of lung inin vivostudies. Conversely, overexpression ofEZH2significantly increased lung metastasis and shortened overall survival when compared with control tumours.EZH2-induced CRC cell invasion may depend on down-regulation of vitamin D receptor (VDR), which is considered to be a marker of CRC invasion.EZH2regulates the histone trimethylation of lysine 27 (H3K27me3) in theVDRpromoter. Moreover, we found that STAT3 directly binds to theEZH2promoter and regulates VDR down-regulation in CRC cells. Significant inverse correlations were observed between the expression ofEZH2and pSTAT3 and that of VDR in CRC tissues compared with normal tissue in patients. We show the role ofEZH2in CRC metastasis and identifyVDRas a target gene ofEZH2.EZH2expression may be directly regulated by STAT3, and STAT3 may play an important role inEZH2-mediated VDR down-regulation in CRC. This pathway may provide potential targets in aggressive CRC.