miR675 upregulates long noncoding RNA H19 through activating EGR1 in human liver cancer.
miR675 upregulates long noncoding RNA H19 through activating EGR1 in human liver cancer.
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miR675通过激活人肝癌中的EGR1上调长链非编码RNA H19
DOI：
10.18632/oncotarget.5579
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发表时间：
2015-10-13
期刊：
影响因子：
--
通讯作者：
Lu D
中科院分区：
文献类型：
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作者：
Li H;Li J;Jia S;Wu M;An J;Zheng Q;Zhang W;Lu D
microRNA（miRNAs）是一类短的非编码RNA，通过影响mRNA的稳定性和翻译，参与多细胞生物体中基因表达的转录后调控。嵌入H19第一外显子的miR 675与人类癌症的发展有关。在此，我们证明了miR 675过表达促进和沉默miR 675在体外和体内减弱肝癌细胞生长。在机制上，miR 675抑制人肝癌细胞中异染色质1亚型HP 1 α的表达，这导致总组蛋白H3赖氨酸9三甲基化（H3 K9 me 3）、组蛋白H3赖氨酸27三甲基化（H3 K27 me 3）的显著降低和组蛋白H3赖氨酸27乙酰化（H3 K27 Ac）的增加。值得注意的是，H3 K9 me 3和H3 K27 me 3的显著减少以及H3 K27 Ac在EGR 1的启动子区域上占据的增加触发EGR 1转录、翻译、类小泛素化和激活，其上调lincRNA H19。引人注目的是，H19可以诱导和激活肿瘤特异性丙酮酸激酶M2（PKM 2），其对于肿瘤发生期间其二聚体中的瓦尔堡效应和其三聚体中的基因表达是必需的。我们的研究结果表明，miR 675参与了H3 K9 me 3，H3 K27 me 3和H3 K27 Ac在肝癌发生过程中的基因表达和功能的表观遗传调控（例如C-myc，Pim 1，Ras，CyclinD 1，RB 1）。这些发现揭示了miR 675-HP 1 α-EGR 1-H19-PKM 2级联信号通路在肝癌中的意义。
microRNAs (miRNAs) are short non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miR675, embedded in H19's first exon, had been linked to the development of human cancers. Herein, we demonstrate miR675 overexpression promotes and silencing miR675 attenuated liver cancer cell growth in vitro and in vivo. Mechanistically, miR675 inhibits the heterochromatin1 isoform HP1α expression in human liver cancer cells which causes a dramatically decrease of the total histone H3 lysine 9 trimethylation (H3K9me3), histone H3 lysine 27 trimethylation (H3K27me3) and a increase of histone H3 lysine 27 acetylation(H3K27Ac). Notably, a significant reduction of the H3K9me3 and H3K27me3 and the increment of H3K27Ac occupancy on the promoter region of EGR1 triggers EGR1 transcription, translation, sumoylation and activation which upregulates lincRNA H19. Strikingly, H19 may induce and activate tumor-specific pyruvate kinase M2 (PKM2) which is essential for the Warburg effect in its dimer and for gene expression in its teramer during tumorigenesis. Our results imply that miR675 is involved in the epigenetic regulation of H3K9me3, H3k27me3 and H3K27Ac for gene expression and function during hepatocarcinogenesis (e.g. C-myc, Pim1, Ras, CyclinD1, RB1). These findings sheds light on the significance of miR675-HP1α-EGR1-H19-PKM2 cascade signaling pathway in liver cancer.