In this study, we identify that ARMC12 increases the EZH2 activity and H3K27me3 levels in an RBBP4-dependent manner, and facilitates the enrichment of PRC2 and H3K27me3 on gene promoters, resulting in transcriptional repression of tumor suppressors affecting the proliferation, invasion, and metastasis of tumor cells, such as CADM145, EGLN346, HRK47, HS6ST348, and SMAD949. The gene discussed is EZH2; the disease is neoplasm.