Table_2_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.

zeste增强子同源物2（Enhancer of zester homolog 2, EZH2）是一种通过多梳抑制复合体2（polycomb repressive complex 2, PRC2）介导组蛋白H3赖氨酸27三甲基化（H3K27me3）的组蛋白甲基转移酶，在卵巢癌中呈高表达状态并可促进肿瘤恶性增殖。然而，维持EZH2高表达的潜在分子机制至今仍未阐明。本研究证实，微小RNA（microRNA, miRNA）可通过结合EZH2信使RNA（mRNA）的3'非翻译区（3′-UTR）抑制其表达；反之，EZH2亦可抑制miRNA的表达。我们确认，EZH2与miRNA之间存在反馈环路，该环路可维持EZH2的高表达水平，进而在体内外促进卵巢癌的恶性增殖。进一步研究通过染色质免疫沉淀（chromatin immunoprecipitation, CHIP）验证发现，EZH2可通过PRC2通路抑制miRNA的表达，同时EZH2可下调p21、p53及RUNX3的蛋白表达。上述结果提示，EZH2可通过H3K27me3通路抑制Et-miRNAs（EZH2靶向miRNA）的表达，从而形成EZH2-miRNA正反馈环路，该环路可维持EZH2的高表达状态，并通过调控细胞增殖相关蛋白的表达促进癌细胞的恶性增殖。