YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving the gene EWSR1 and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis, but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of the RASSF1 locus (a regulator of the Hippo pathway) was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the pro-tumorigenic isoform RASSF1C, which promotes YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be explained partly by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

中文翻译：

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河马途径效应器YAP1 / TAZ诱导EWS-FLI1对抗基因签名，并与尤文肉瘤的疾病进展相关。

YAP1和TAZ（WWTR1）癌蛋白是河马肿瘤抑制途径的最终转化子。该通路的失调导致YAP1 / TAZ活化，促进包括肉瘤在内的多种恶性肿瘤类型的肿瘤发生。然而，在河马途径的核心组成部分内的致癌突变并不常见。尤文氏肉瘤（EwS）是一种突变率低的小儿癌症，其特征在于经典融合涉及基因EWSR1和FLI1作为最常见的伴侣。融合蛋白是致癌作用的有效驱动力，但是继发性改变却很少，对决定复发或进展风险的其他生物学因素知之甚少。我们已经观察到YAP1 / TAZ在EwS细胞系中的表达和转录活性。对55个主要人类EwS样品的分析表明，高YAP1 / TAZ表达与疾病进展相关，并预测结果较差。我们未在河马途径相关基因座中观察到复发性SNV或拷贝数增减。但是，与间充质干细胞（间质干细胞，EwS的来源）相比，在EwS细胞系中观察到RASSF1基因座（Hippo途径的调节剂）的差异CpG甲基化。RASSF1的超甲基化与肿瘤抑制同工型RASFF1A的转录沉默和促肿瘤同工型RASSF1C的转录激活有关，后者促进YAP1 / TAZ激活。击倒YAP1 / TAZ会降低EwS细胞的增殖和侵袭能力，并揭示YAP1 / TAZ转录活性与EWS-FLI1转录特征成反比。这种转录拮抗作用可以部分通过EWS-FLI1介导的TAZ转录抑制来解释。因此，YAP1 / TAZ可能会覆盖融合蛋白诱导的转录程序，从而有助于通过融合蛋白的动态波动确定的表型可塑性，这是最近提出的在EwS中传播疾病的模型。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。YAP1 / TAZ可能会覆盖融合蛋白诱导的转录程序，从而促进由融合蛋白的动态波动确定的表型可塑性，这是最近提出的在EwS中传播疾病的模型。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。YAP1 / TAZ可能会覆盖融合蛋白诱导的转录程序，从而促进由融合蛋白的动态波动确定的表型可塑性，这是最近提出的在EwS中传播疾病的模型。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。