HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling.
HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling.
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DOI：
10.1038/srep23521
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发表时间：
2016-03-24
影响因子：
4.6
通讯作者：
Fan H
中科院分区：
文献类型：
--
作者：
Hu JJ;Song W;Zhang SD;Shen XH;Qiu XM;Wu HZ;Gong PH;Lu S;Zhao ZJ;He ML;Fan H
众所周知，HBx在与B型肝炎病毒（HBV）感染相关的肝癌发生中起主要作用。然而，很少有人知道它在调节长链非编码RNA（lncRNA）中的作用，lncRNA是一大组调节哺乳动物细胞中各种生物学过程（包括致癌作用）的转录本。在这里，我们报告，HBx上调UCA 1基因和下调p27基因在肝LO 2细胞。进一步的研究表明，上调的UCA 1通过促进肝细胞和肝癌细胞中的CDK 2的G1/S转变来促进细胞生长。在表达HBx的肝细胞和肝癌细胞中敲低UCA 1通过升高裂解的caspase-3和caspase-8导致凋亡细胞显著增加。更重要的是，发现UCA 1与zeste同源物2（EZH 2）的增强子物理相关，EZH 2通过p27 Kip 1启动子上的组蛋白甲基化（H3 K27 me 3）抑制p27 Kip 1。我们还表明，UCA 1在肝癌细胞中的敲低抑制裸鼠的肿瘤发生。在临床研究中发现，与HBx阴性组相比，UCA 1在HBx阳性组组织中频繁上调，且UCA 1与p27 Kip 1水平呈负相关。我们的研究结果表明，HBx-UCA 1/EZH 2-p27 Kip 1轴信号转导是肝癌发生的重要机制，是HCC的潜在靶点。
It is well accepted that HBx plays the major role in hepatocarcinogenesis associated with hepatitis B virus (HBV) infections. However, little was known about its role in regulating long noncoding RNAs (lncRNAs), a large group of transcripts regulating a variety of biological processes including carcinogenesis in mammalian cells. Here we report that HBx upregulates UCA1 genes and downregulates p27 genes in hepatic LO2 cells. Further studies show that the upregulated UCA1 promotes cell growth by facilitating G1/S transition through CDK2 in both hepatic and hepatoma cells. Knock down of UCA1 in HBx-expressing hepatic and hepatoma cells resulted in markedly increased apoptotic cells by elevating the cleaved caspase-3 and caspase-8. More importantly, UCA1 is found to be physically associated with enhancer of zeste homolog 2 (EZH2), which suppresses p27Kip1 through histone methylation (H3K27me3) on p27Kip1 promoter. We also show that knockdown of UCA1 in hepatoma cells inhibits tumorigenesis in nude mice. In a clinic study, UCA1 is found to be frequently up-regulated in HBx positive group tissues in comparison with the HBx negative group, and exhibits an inverse correlation between UCA1 and p27Kip1 levels. Our findings demonstrate an important mechanism of hepatocarcinogenesis through the signaling of HBx-UCA1/EZH2-p27Kip1 axis, and a potential target of HCC.