Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis
Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis
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DOI：
10.1073/pnas.1420005112
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发表时间：
2015-06-30
影响因子：
11.1
通讯作者：
Simon, M. Celeste
中科院分区：
文献类型：
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作者：
Eisinger-Mathason, T. S. Karin;Mucaj, Vera;Simon, M. Celeste
导致成人软组织肉瘤形成的遗传畸变在很大程度上是未知的，对于这种复杂和异质性疾病家族，迫切需要靶向治疗。在这里，我们报告说，在许多软组织肉瘤中，Hippo通路失调，导致效应分子是相关蛋白（雅普）的表达升高。基于从人类肉瘤患者收集的数据，一种新的本地小鼠模型，和机制分析，我们确定YAP依赖的转录因子叉头盒M1（FOXM 1）的表达是必要的细胞增殖/肿瘤发生在一个子集的软组织肉瘤。值得注意的是，FOXM 1通过TEAD 1直接与雅普转录复合物相互作用，导致许多关键促增殖靶点的共调节，从而促进肉瘤进展。最后，FOXM 1的药理学抑制在体内减小肿瘤大小，使得FOXM 1成为治疗某些肉瘤亚型的有吸引力的治疗靶点。
Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes.