Department of Thoracic Oncology II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, People's Republic of China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, California.
Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.
Am J Pathol. 2019 May;189(5):1077-1090. doi: 10.1016/j.ajpath.2019.01.016. Epub 2019 Feb 19.
Hepatoblastoma (HB) is the most common type of pediatric liver cancer. Activation of yes-associated protein (YAP) has been implicated in HB molecular pathogenesis. The transcriptional co-activator Yap regulates downstream gene expression through interaction with the TEA domain (TEAD) proteins. Nonetheless, YAP also displays functions that are independent of its transcriptional activity. The underlying molecular mechanisms by which Yap promotes HB development remain elusive. In the current study, we demonstrated that blocking TEAD function via the dominant-negative form of TEAD2 abolishes Yap-driven HB formation in mice and restrains human HB growth in vitro. When TEAD2 DNA-binding domain was fused with virus protein 16 transcriptional activation domain, it synergized with activated β-catenin to promote HB formation in vivo. Among TEAD genes, silencing of TEAD4 consistently inhibited tumor growth and Yap target gene expression in HB cell lines. Furthermore, TEAD4 mRNA expression was significantly higher in human HB lesions when compared with corresponding nontumorous liver tissues. Human HB specimens also exhibited strong nuclear immunoreactivity for TEAD4. Altogether, data demonstrate that TEAD-mediated transcriptional activity is both sufficient and necessary for Yap-driven HB development. TEAD4 is the major TEAD isoform and Yap partner in human HB. Targeting TEAD4 may represent an effective treatment option for human HB.
肝母细胞瘤 (HB) 是最常见的儿童肝癌类型。YAP 的激活已被牵连到 HB 的分子发病机制中。转录共激活因子 yap 通过与 TEA 结构域 (TEAD) 蛋白相互作用来调节下游基因表达。尽管如此，YAP 还具有与其转录活性无关的功能。yap 促进 HB 发展的潜在分子机制仍不清楚。在本研究中，我们证明了通过 TEAD2 的显性失活形式阻断 TEAD 功能可在小鼠中消除 yap 驱动的 HB 形成，并抑制体外人 HB 的生长。当 TEAD2 DNA 结合域与病毒蛋白 16 转录激活结构域融合时，它与激活的β-catenin 协同促进体内 HB 的形成。在 TEAD 基因中，沉默 TEAD4 一致抑制 HB 细胞系中的肿瘤生长和 yap 靶基因表达。此外，与相应的非肿瘤性肝组织相比，TEAD4 mRNA 表达在人 HB 病变中显著升高。人类 HB 标本也显示出强烈的核 TEAD4 免疫反应性。总的来说，数据表明 TEAD 介导的转录活性对于 yap 驱动的 HB 发展是充分和必要的。TEAD4 是人类 HB 中主要的 TEAD 同工型和 yap 伴侣。靶向 TEAD4 可能是治疗人类 HB 的有效选择。
