Integrative genomics analysis reveals the multilevel dysregulation and oncogenic characteristics of TEAD4 in gastric cancer
Integrative genomics analysis reveals the multilevel dysregulation and oncogenic characteristics of TEAD4 in gastric cancer
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DOI：
10.1093/carcin/bgt409
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发表时间：
2014-05-01
期刊：
影响因子：
4.7
通讯作者：
Kim, Seon-Young
中科院分区：
文献类型：
--
作者：
Lim, Byungho;Park, Jong-Lyul;Kim, Seon-Young
肿瘤发生是针对发生在基因组、表观基因组、转录组和蛋白质组水平的有害扰动的多步骤防御机制失败的结果。为了揭示以前未被识别的基因在胃癌（GC）中经历多级扰动，我们使用两种最近开发的工具：MENT和GENT整合了表观基因组学和转录组学方法。该整合分析显示，9个Hippo通路相关基因，包括组分[FAT、JUB、LATS 2、TEA结构域家族成员4（TEAD 4）和YAP 1]和靶点（CRIM 1、CYR 61、CTGF和ITGB 2），在启动子CpG位点同时低甲基化并在GC组织中过表达。特别是，与正常对照相比，108例韩国人胃癌组织中，Hippo通路组分和靶点之间的联系TEAD 4在CpG位点cg 21637033显著低甲基化（P = 3.8 x 10（-）（20））和过表达（P = 5.2 x 10（-）（10））。TEAD 4启动子甲基化水平降低与不良结局显著相关，包括肿瘤大小大，肿瘤分级高和生存率低。与正常组织相比，TEAD 4蛋白在53例GC患者的肿瘤细胞核中与YAP 1沿着更频繁地被发现，证明了该蛋白的翻译后激活。此外，TEAD 4的敲低导致GC细胞在体外和体内的生长减少。最后，染色质免疫沉淀测序和微阵列分析揭示了TEAD 4及其新靶点（ADM，ANG，ARID 5 B，CALD 1，EDN 2，FSCN 1和OSR 2）的致癌特性，这些靶点参与细胞增殖和迁移。总之，TEAD 4在表观遗传、转录和翻译后水平的多层次扰动可能有助于GC的发展。
Tumorigenesis is a consequence of failures of multistep defense mechanisms against deleterious perturbations that occur at the genomic, epigenomic, transcriptomic and proteomic levels. To uncover previously unrecognized genes that undergo multilevel perturbations in gastric cancer (GC), we integrated epigenomic and transcriptomic approaches using two recently developed tools: MENT and GENT. This integrative analysis revealed that nine Hippo pathway-related genes, including components [FAT, JUB, LATS2, TEA domain family member 4 (TEAD4) and Yes-associated protein 1 (YAP1)] and targets (CRIM1, CYR61, CTGF and ITGB2), are concurrently hypomethylated at promoter CpG sites and overexpressed in GC tissues. In particular, TEAD4, a link between Hippo pathway components and targets, was significantly hypomethylated at CpG site cg21637033 (P = 3.8 x 10(-) (20)) and overexpressed (P = 5.2 x 10(-) (10)) in 108 Korean GC tissues compared with the normal counterparts. A reduced level of methylation at the TEAD4 promoter was significantly associated with poor outcomes, including large tumor size, high-grade tumors and low survival rates. Compared with normal tissues, the TEAD4 protein was more frequently found in the nuclei of tumor cells along with YAP1 in 53 GC patients, demonstrating the posttranslational activation of this protein. Moreover, the knockdown of TEAD4 resulted in the reduced growth of GC cells both in vitro and in vivo. Finally, chromatin immunoprecipitation-sequencing and microarray analysis revealed the oncogenic properties of TEAD4 and its novel targets (ADM, ANG, ARID5B, CALD1, EDN2, FSCN1 and OSR2), which are involved in cell proliferation and migration. In conclusion, the multilevel perturbations of TEAD4 at epigenetic, transcriptional and posttranslational levels may contribute to GC development.