The dysregulation of long and short (microRNA) expression in cancer has been well documented. However, the underlying mechanism is not fully explored. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and is overexpressed in cancer. To explore the role of EZH2 in regulating miRNAs expression, we performed genomic miRNAs profiling in pancreatic duct adenocarcinoma (PDAC) cells with EZH2 inhibition. MiR-218 was repressed by EZH2 in PDAC cells and UDP-glycosyltransferase 8 (UGT-8) was identified as a novel target of miR-218. We identified a novel EZH2/miR-218/UGT-8 pathway associated with progression of PDAC. We also found that miR-34a was regulated by EZH2 in PDAC cells and demonstrated that EZH2 suppressed miR-34a expression through trimethylation of H3K27 and heterochromatin formation. 

Most recently, we demonstrate that two lncRNA frequently downregulated in hepatocellular carcinoma (HCC) function as tumor suppressors and are epigenetically silenced by EZH2. lncRNAs TCAM1P-004 and RP11-598D14.1 were inhibited by EZH-mediated trimethylation of H3K27me3 at their promoters. Downregulation of TCAM1P-004 and RP11-598D14.1 were frequently observed in HCC tumors. Both lncRNAs inhibited cell growth, cell survival, and transformation in HCC cells in vitro as well as tumor formation in vivo. Using RNA pull-down and mass spectrometry, we demonstrated that TCAM1P-004 bound IGF2BP1 and HIST1H1C, while RP11-598D14.1 bound IGF2BP1 and STAU1. These lncRNA-protein interactions were critical in regulating p53, MAPK, and HIF1-α pathways that promoted cell proliferation in HCC. 

We previously identified a small molecule modulator of miR-34a which could selectively restore the expression of miR-34a in HCC cells. The in vitro and in vivo anti-cancer activities of the small molecule were demonstrated in cell and animal models. Taken together, EZH2 plays important roles in regulating non-coding RNA expression in cancer. Targeting EZH2 and/or its regulated ncRNAs represent novel therapeutic strategies for cancer.