To investigate the epigenetic mechanism leading to PPP2R2B downregulation in breast cancer, we treated SKBR3 and UACC812 cells with a series of epigenetic compounds including DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (5AZA), HDAC inhibitor Trichostatin A (TSA), and histone methyltransferase EZH2 inhibitors EPZ-6438 (hereafter EPZ) and GSK126. This evidence concerns the gene EZH2 and breast cancer.