Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 98195, USA.
Genes Dev. 2020 Aug 1;34(15-16):1051-1064. doi: 10.1101/gad.338681.120. Epub 2020 Jul 16.
YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several 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 gene fusions , , , and 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.
YAP1 是 Hippo 信号通路的转录共激活因子和主要效应因子，该通路与人类癌症的发生有因果关系。在各种人类癌症中已经鉴定出几种基因融合，鉴定这些基因融合家族的基本成分具有重要的治疗价值。在这里，我们表明基因融合 、 、 和 在小鼠中具有致癌性。通过报告基因检测、RNA-seq、ChIP-seq 和功能丧失突变，我们可以证明所有这些 YAP1 融合蛋白都发挥了 TEAD 依赖性 YAP 活性，而一些融合蛋白还发挥了 C'-末端融合伴侣的活性。由于 YAP1 融合蛋白的核定位和降解的稳定性，不同 YAP1 融合蛋白的 YAP 活性抵抗负性 Hippo 通路调节。这些致癌 YAP1 融合蛋白的 TEAD 结合域的遗传破坏足以抑制体内肿瘤形成，而 YAP1-TEAD 相互作用的药理学抑制抑制了体外表达 YAP1 融合蛋白的细胞系的生长。这些结果强调了这些基因融合中发现的依赖 TEAD 的 YAP 活性对于致癌作用至关重要，并暗示这些 YAP 功能可能成为 YAP1 融合阳性肿瘤的潜在治疗靶点。
