School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.
Cancer Res. 2019 Apr 1;79(7):1305-1317. doi: 10.1158/0008-5472.CAN-18-1659. Epub 2019 Feb 4.
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 as well as tumor formation . 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 HIF1α 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 TCAM1P-004 and RP11-598D14.1 hinders the formation of tumor suppressor lncRNA-protein complexes and subsequently promotes HCC growth.
长链非编码 RNA（lncRNA）在癌症的发展中起着至关重要的作用，包括肝细胞癌（HCC）。然而，它们失调的机制在很大程度上仍未被探索。在这项研究中，我们报告了两种在 HCC 中经常下调的 lncRNA 作为肿瘤抑制因子发挥作用，并被组蛋白甲基转移酶 EZH2 表观沉默。lncRNAs TCAM1P-004 和 RP11-598D14.1 的启动子被 EZH 介导的 H3K27me3 三甲基化抑制。与相邻的正常组织相比，TCAM1P-004 和 RP11-598D14.1 在 HCC 肿瘤中经常下调。TCAM1P-004 和 RP11-598D14.1 的下调在 HCC 细胞中抑制细胞生长、细胞存活和转化以及肿瘤形成。使用 RNA 下拉和质谱分析，我们证明 TCAM1P-004 结合 IGF2BP1 和 HIST1H1C，而 RP11-598D14.1 结合 IGF2BP1 和 STAU1。这些 lncRNA-蛋白相互作用对于调节 p53、MAPK 和 HIF1α 途径至关重要，这些途径促进了 HCC 中的细胞增殖。EZH2 的过表达对于抑制 TCAM1P-004 和 RP11-598D14.1 至关重要，并且 EZH2-TCAM1P-004/RP11-598D14.1 调节的途径在人类 HCC 中普遍存在。TCAM1P-004 和 RP11-598D14.1 的异常抑制通过破坏与 IGF2BP1、HIST1H1C 和 STAU1 的相互作用，导致其肿瘤抑制作用丧失，从而促进 HCC 的发展和进展。总的来说，这些发现表明 TCAMP1P-004 和 RP11-598D14.1 在抑制肿瘤生长中的作用，并表明 EZH2 可能是 HCC 的治疗靶点。意义：EZH2 介导的 lncRNAs TCAM1P-004 和 RP11-598D14.1 的丧失阻碍了肿瘤抑制 lncRNA-蛋白复合物的形成，随后促进了 HCC 的生长。
