Mechanistically, we provide evidences that the O-GlcNAcylated form of EZH2 prevents the transcription of UNC5A in human colon cancer cells through aberrant O-GlcNAcylation and abnormal targeting of the PRC2 complex onto its promoter, thus linking nutrition to downregulation of UNC5A in CRC. Here, EZH2 is linked to colonic neoplasm.