UNLABELLED:The MYC oncogene is overexpressed in hepatocellular carcinoma (HCC) and has been associated with widespread microRNA (miRNA) repression; however, the underlying mechanisms are largely unknown. Here, we report that the c-Myc oncogenic transcription factor physically interacts with enhancer of zeste homolog 2 (EZH2), a core enzymatic unit of polycomb repressive complex 2 (PRC2). Furthermore, miR-101, an important tumor-suppressive miRNA in human hepatocarcinomas, is epigenetically repressed by PRC2 complex in a c-Myc-mediated manner. miR-101, in turn, inhibits the expression of two subunits of PRC2 (EZH2 and EED), thus creating a double-negative feedback loop that regulates the process of hepatocarcinogenesis. Restoration of miR-101 expression suppresses multiple malignant phenotypes of HCC cells by coordinate repression of a cohort of oncogenes, including STMN1, JUNB, and CXCR7, and further increases expression of endogenous miR-101 by inhibition of PRC2 activation. In addition, co-overexpression of c-Myc and EZH2 in HCC samples was closely associated with lower expression of miR-101 (P < 0.0001) and poorer prognosis of HCC patients (P < 0.01). CONCLUSIONS:c-Myc collaborates with EZH2-containing PRC2 complex in silencing tumor-suppressive miRNAs during hepatocarcinogenesis and provides promising therapeutic candidates for human HCC.

译文

UNLABELLED:MYC癌基因在肝细胞癌(HCC)中过表达,并与广泛的microRNA(miRNA)抑制有关。但是,基本机制尚不清楚。在这里,我们报告c-Myc致癌转录因子与zeste同源物2(EZH2)(多梳抑制复合物2(PRC2)的核心酶单元)的增强子发生物理相互作用。此外,miR-101是人类肝癌中一种重要的肿瘤抑制性miRNA,它以c-Myc介导的方式被PRC2复合物表观遗传抑制。反过来,miR-101抑制PRC2的两个亚基(EZH2和EED)的表达,从而产生了一个双负反馈回路,可调节肝癌的发生过程。 miR-101表达的恢复可通过协调抑制包括STMN1,JUNB和CXCR7在内的一系列致癌基因来抑制HCC细胞的多种恶性表型,并通过抑制PRC2激活进一步增加内源性miR-101的表达。此外,HCC样本中c-Myc和EZH2的共过量表达与miR-101的较低表达(P <0.0001)和HCC患者的预后较差(P <0.01)密切相关。
结论:c-Myc与含EZH2的PRC2复合物协同作用,在肝癌发生过程中沉默肿瘤抑制性miRNA,并为人类HCC提供了有希望的治疗候选物。

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