Project description:Genomic sequencing of hepatocellular carcinoma (HCC) uncovers a paucity of actionable mutations, underscoring the necessity to exploit epigenetic vulnerabilities for therapeutics. In HCC, EZH2-mediated H3K27me3 represents a major oncogenic chromatin modification, but how it modulates the therapeutic vulnerability of signaling pathways remains unknown. Here, we identified that EZH2 maintains H3K27 methylome through epigenetic silencing of specific gene sets. ChIP-seq revealed enrichment of EZH2/H3K27me3 at silenced loci in HBx-transgenic (TG) mouse-derived HCCs, including tumor suppressors whose down-regulation significantly correlated with EZH2 overexpression and poor survival of HCC patients. Defining the aberrant chromatin landscape of HCC sheds light into the mechanistic basis of effective EZH2-targeted inhibition.
Project description:The molecular mechanisms of carcinogenesis have been deeply studied benefit from the highly developing biotechnologies. Here we used high throughput sequencing method to capture the global binding profiles on RNA and DNA of EZH2 and JARID2 in liver normal (THLE-2) and carcinoma (HepG2) cells, respectively. We found that EZH2 and JARID2 showed distinct binding profile in HepG2 and THLE-2 cells. By binding to the primary RNAs, bound transcripts of EZH2 and JARID2 in HepG2 showed significantly increased transcriptional level in hepatocellular carcinoma (HCC) patients. They bound transcripts were also highly related to the HCC development by performing gene set enrichment analysis (GSEA). By exploring the DNA binding profile, we also detected similar phenomena that EZH2 could increase the transcriptional level of bound genes in HepG2 cells, showing PRC2-independent functions in liver cancer cells. Integrating analysis of the RNA and DNA binding profile showed EZH2 could independent function at the transcriptional and post-transcriptional stages. In summary, we proposed that the novel regulatory functions of EZH2 and JARID2 that may promote the cancer development in carcinoma liver cells.