Abstract
EZH2, a histone methyltransferase, has been shown to involve in cancer development and progression via epigenetic regulation of tumor suppressor microRNAs, whereas BMI1, a driver of hepatocellular carcinoma (HCC), is a downstream target of these microRNAs. However, it remains unclear whether EZH2 can epigenetically regulate microRNA expression to modulate BMI1-dependent hepatocarcinogenesis. Here, we established that high EZH2 expression correlated with enhanced tumor size, elevated metastasis, increased relapse, and poor prognosis in HCC patients. Further clinical studies revealed that EZH2 overexpression was positively correlated to its gene copy number gain/amplification in HCC. Mechanistically, EZH2 epigenetically suppressed miR-200c expression both in vitro and in vivo, and more importantly, miR-200c post-transcriptionally regulated BMI1 expression by binding to the 3′-UTR region of its mRNA. Furthermore, miR-200c overexpression inhibits the growth of HCC cells in vivo. Silencing miR-200c rescued the tumorigenicity of EZH2-depleted HCC cells, whereas knocking down BMI1 reduced the promoting effect of miR-200c depletion on HCC cell migration. Finally, combination treatment of EZH2 and BMI1 inhibitors further inhibited the viability of HCC cells compared with the cells treated with EZH2 or BMI1 inhibitor alone. Our findings demonstrated that alteration of EZH2 gene copy number status induced BMI1-mediated hepatocarcinogenesis via epigenetically silencing miR-200c, providing novel therapeutic targets for HCC treatment.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer mortality worldwide[1]
High EZH2 expression strongly correlates with poor prognosis in HCC patients Previous studies suggest that EZH2 has an important role in cancer development and progression[19,20]
To determine its oncogenic role in HCC, we first examined the expression level of EZH2 in multiple cancers by analyzing GEPIA (Gene Expression Profiling Interactive Analysis) data set and RNA-seq data set retrieved from The Cancer Genome Atlas (TCGA) database
Summary
Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer mortality worldwide[1]. A multiple kinase inhibitor, Recent studies have shown that polycomb repressive complexes (PRC) play an important role in maintaining stem cell behavior and cancer biology[3,4]. They consist of two major classes, PRC1 and PRC2, that can collaboratively regulate gene expression by modifying chromatin structures[5]. EZH2, an enzymatic component of PRC2, can silence its target genes by inducing the trimethylation of lysine 27 on histone 3 (H3K27me3)[6,7]. Afterwards, PRC1, composed of BMI1, RING1 and RING2, recognizes the H3K27me[3] mark produced by the PRC2 complex and mono-ubiquitinates K119 on
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