Abstract
Enhancer of zeste homolog 2 (EZH2), a dynamic chromatin regulator in cancer, represents a potential therapeutic target showing early signs of promise in clinical trials. EZH2 ChIP sequencing data in 19 cell lines and RNA sequencing data in ten cancer types were downloaded from GEO and TCGA, respectively. Integrated ChIP sequencing analysis and co-expressing analysis were conducted and both mRNA and long noncoding RNA (lncRNA) targets were detected. We detected a median of 4,672 mRNA targets and 4,024 lncRNA targets regulated by EZH2 in 19 cell lines. 20 mRNA targets and 27 lncRNA targets were found in all 19 cell lines. These mRNA targets were enriched in pathways in cancer, Hippo, Wnt, MAPK and PI3K-Akt pathways. Co-expression analysis confirmed numerous targets, mRNA genes (RRAS, TGFBR2, NUF2 and PRC1) and lncRNA genes (lncRNA LINC00261, DIO3OS, RP11-307C12.11 and RP11-98D18.9) were potential targets and were significantly correlated with EZH2. We predicted genome-wide potential targets and the role of EZH2 in regulating as a transcriptional suppressor or activator which could pave the way for mechanism studies and the targeted therapy of EZH2 in cancer.
Highlights
Dynamic regulation of chromatin regulators at enhancers and promoters plays an important role in modulation of gene expression and cell fate determination [1, 2]
We detected a median of 4,672 mRNA targets and 4,024 long noncoding RNA (lncRNA) targets regulated by Enhancer of zeste homolog 2 (EZH2) in cell lines. mRNA targets and 27 lncRNA targets were found in all 19 cell lines
The results showed that EZH2 binding sites in most cell lines were centered on the promoter region ( 3kb to the TSS region) (Figure 1A)
Summary
Dynamic regulation of chromatin regulators at enhancers and promoters plays an important role in modulation of gene expression and cell fate determination [1, 2]. EZH2, the catalytic subunit of Polycomb repressive complex 2 (PRC2), methylates lysine 27 of histone H3 (H3K27) to promote transcriptional silencing [3]. Converging lines of investigation have implicated that EZH2 is likely to be an important mediator of tumor cell plasticity and involves in development and progression of serval cancers. Given its role as a transcriptional regulator, researchers focus on the identification of EZH2 regulated target genes or pathways with great efforts. In prostate cancer and breast cancer, EZH2 has been shown to repress the expression of E-cadherin [8] and RUNX3 [9], resulted in promotion of EMT and invasive phenotype and increased cell proliferation, respectively. Ectopic EZH2 expression has been found to confer a proliferative advantage upon noncancerous cells [5]
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