Genome-Wide Screening and Functional Analysis Identifies Tumor Suppressor Long Noncoding RNAs Epigenetically Silenced in Hepatocellular Carcinoma
Genome-Wide Screening and Functional Analysis Identifies Tumor Suppressor Long Noncoding RNAs Epigenetically Silenced in Hepatocellular Carcinoma
复制标题
全基因组筛选和功能分析鉴定了肝细胞癌中表观遗传沉默的抑癌长链非编码RNA
DOI：
10.1158/0008-5472.can-18-1659
复制
发表时间：
2019-04-01
期刊：
影响因子：
11.2
通讯作者：
Chen, Yangchao
中科院分区：
文献类型：
--
作者：
Xu, Feiyue;Li, Chi Han;Chen, Yangchao
长链非编码RNA（lncRNA）在包括肝细胞癌（HCC）在内的癌症的发展中起着关键作用。然而，其放松管制的机制在很大程度上仍未得到探索。在这项研究中，我们报告了两个lncRNA在HCC中经常下调，作为肿瘤抑制因子，并被组蛋白甲基转移酶EZH 2表观遗传学沉默。lncRNA TCAM 1 P-004和RP 11 -598D14.1在其启动子处被EZH介导的H3 K27 me 3三甲基化抑制。与邻近正常组织相比，在HCC肿瘤中经常观察到TCAM 1 P-004和RP 11 - 598 D14.1的下调。这两种lncRNA在体外抑制HCC细胞的细胞生长、细胞存活和转化以及在体内抑制肿瘤形成。使用RNA下拉和质谱，我们证明TCAM 1 P-004结合IGF 2BP 1和HIST 1H 1C，而RP 11 - 598 D14.1结合IGF 2BP 1和STAU 1。这些lncRNA-蛋白质相互作用在调节促进HCC细胞增殖的p53、MAPK和HIF 1 α途径中至关重要。EZH 2的过表达在抑制TCAM 1 P-004和RP 11 -598D14.1中是关键的，并且EZH 2-TCAM 1 P-004/RP 11 -598D14.1调节的通路在人类HCC中是普遍的。TCAM 1 P-004和RP 11 - 598 D14.1的异常抑制通过破坏与IGF 2BP 1、HIST 1H 1C和STAU 1的相互作用而导致其肿瘤抑制作用的丧失，这反过来促进了HCC的发生和进展。总的来说，这些发现证明了TCAMP 1 P-004和RP 11 -598D14.1在抑制肿瘤生长中的作用，并表明EZH 2可能作为HCC的治疗靶点。意义：EZH 2介导的lncRNA TCAM 1 P004和RP 11 -598D14.1的丢失阻碍了肿瘤抑制lncRNA-蛋白复合物的形成，随后促进HCC生长。
Long noncoding RNAs (lncRNA) play critical roles in the development of cancer, including hepatocellular carcinoma (HCC). However, the mechanisms underlying their deregulation remain largely unexplored. In this study, we report that two lncRNAs frequently downregulated in HCC function as tumor suppressors and are epigenetically silenced by histone methyltransferase EZH2. lncRNAs TCAM1P-004 and RP11-598D14.1 were inhibited by EZH-mediated trimethylation of H3K27me3 at their promoters. Downregulation of TCAM1P-004 and RP11-598D14.1 was frequently observed in HCC tumors compared with adjacent normal tissues. Both lncRNAs inhibited cell growth, cell survival, and transformation in HCC cells in vitro as well as tumor formation in vivo. Using RNA pull-down and mass spectrometry, we demonstrated that TCAM1P-004 bound IGF2BP1 and HIST1H1C, whereas RP11-598D14.1 bound IGF2BP1 and STAU1. These lncRNA-protein interactions were critical in regulating p53, MAPK, and HIF1 alpha pathways that promoted cell proliferation in HCC. Overexpression of EZH2 was critical in repressing TCAM1P-004 and RP11-598D14.1, and EZH2-TCAM1P-004/RP11-598D14.1-regulated pathways were prevalent in human HCC. Aberrant suppression of TCAM1P-004 and RP11-598D14.1 led to loss of their tumor-suppressive effects by disrupting the interaction with IGF2BP1, HIST1H1C, and STAU1, which in turn promoted HCC development and progression. Collectively, these findings demonstrate the role of TCAMP1P-004 and RP11-598D14.1 in suppressing tumor growth and suggest that EZH2 may serve as a therapeutic target in HCC.Significance: EZH2-mediated loss of lncRNAs TCAM1P004 and RP11-598D14.1 hinders the formation of tumor suppressor lncRNA-protein complexes and subsequently promotes HCC growth.