YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, and YAP1-SS18 are oncogenic in mice. Using reporter assays, RNA-seq, ChIP-seq, and loss-of-function mutations, we can show that all of these YAP1 fusion proteins exert TEAD-dependent YAP activity, while some also exert activity of the C′-terminal fusion partner. The YAP activity of the different YAP1 fusions is resistant to negative Hippo pathway regulation due to constitutive nuclear localization and resistance to degradation of the YAP1 fusion proteins. Genetic disruption of the TEAD-binding domain of these oncogenic YAP1 fusions is sufficient to inhibit tumor formation in vivo, while pharmacological inhibition of the YAP1–TEAD interaction inhibits the growth of YAP1 fusion-expressing cell lines in vitro. These results highlight TEAD-dependent YAP activity found in these gene fusions as critical for oncogenesis and implicate these YAP functions as potential therapeutic targets in YAP1 fusion-positive tumors.

中文翻译：

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肿瘤相关的YAP1融合的比较确定了一组复发的对肿瘤发生至关重要的功能。

YAP1是Hippo信号通路的转录共激活因子和主要效应物，它与人类癌症有因果关系。已经在各种人类癌症中鉴定出几种YAP1基因融合体，并且鉴定该基因融合体家族的基本成分具有重要的治疗价值。在这里，我们表明YAP1基因融合YAP1-MAMLD1，YAP1-FAM118B，YAP1-TFE3，和YAP1-SS18对小鼠有致癌作用。使用报告基因分析，RNA-seq，ChIP-seq和功能丧失突变，我们可以证明所有这些YAP1融合蛋白均具有TEAD依赖性YAP活性，而有些还具有C'端融合伴侣的活性。由于组成性核定位和对YAP1融合蛋白降解的抵抗，不同YAP1融合的YAP活性可抵抗负的Hippo途径调控。这些致癌的YAP1融合物的TEAD结合域的遗传破坏足以抑制体内肿瘤的形成，而药理学上抑制YAP1-TEAD相互作用的作用则在体外抑制了表达YAP1融合的细胞系的生长。