Table_3_EZH2-miRNA Positive Feedback Promotes Tumor Growth in Ovarian Cancer.xlsx

Enhancer of zester homolog 2 (EZH2), a histone methyl transferase that mediates H3K27me3 through polycomb repressive complex 2 (PRC2), is overexpressed in ovarian cancer and promotes malignant proliferation. However, the underlying mechanism of maintaining high EZH2 expression remains elusive. Here we showed that microRNA(miRNA) inhibited EZH2 by binding to the 3′-UTR of EZH2 mRNA; conversely, EZH2 can inhibit miRNA expression. We confirmed that a feedback loop exists between EZH2 and miRNA that maintained EZH2 overexpression, thus promoting ovarian cancer proliferation in vivo and in vitro. We further explored that EZH2 inhibited miRNA expression through PRC2, as determined by CHIP (chromatin immunoprecipitation), and EZH2 decreased the expression of p21, p53, and RUNX3. These results suggest that EZH2 inhibits the expression of Et-miRNAs (EZH2-targeting miRNAs) through the H3K27me3 pathway, thus forming an EZH2-miRNA positive feedback loop that maintains the high expression of EZH2 and promotes the malignant proliferation of cancer cells by regulating the expression of cell proliferation-related proteins.

增强子同源蛋白2（Enhancer of zester homolog 2，EZH2），一种介导H3K27me3的组蛋白甲基转移酶，通过多梳抑制复合体2（polycomb repressive complex 2，PRC2）发挥作用，其在卵巢癌中表达上调并促进恶性增殖。然而，维持高EZH2表达水平的潜在机制尚不明确。本研究揭示了miRNA（microRNA）通过结合EZH2 mRNA的3'-UTR（3'-非编码区）来抑制EZH2；反之，EZH2也能抑制miRNA的表达。我们证实了EZH2与miRNA之间存在反馈回路，该回路维持EZH2的高表达，从而在体内和体外促进卵巢癌的增殖。我们进一步探究了EZH2通过PRC2抑制miRNA表达，这一发现是通过染色质免疫沉淀（chromatin immunoprecipitation，CHIP）技术得出的，并且EZH2降低了p21、p53和RUNX3的表达。这些结果提示，EZH2通过H3K27me3途径抑制了Et-miRNAs（EZH2靶向miRNAs）的表达，从而形成一个EZH2-miRNA的正反馈回路，维持EZH2的高表达，并通过调节细胞增殖相关蛋白的表达，促进癌细胞的恶性增殖。