Endometrial stromal sarcoma (ESS) is the second most common subtype of uterine mesenchymal cancer, after leiomyosarcoma, and oncogenic fusion proteins are found in many ESS. Our previous studies demonstrated transforming properties and diagnostic relevance of the fusion oncoprotein YWHAE–NUTM2 in high-grade endometrial stromal sarcoma (HG-ESS) and showed that cyclin D1 is a diagnostic biomarker in these HG-ESS. However, YWHAE–NUTM2 mechanisms of oncogenesis and roles in cyclin D1 expression have not been characterized. In the current studies, we show YWHAE-NUTM2 complexes with both BRAF/RAF1 and YAP/TAZ in HG-ESS. These interactions are functionally relevant because YWHAE-NUTM2 knockdown in HG-ESS and other models inhibits RAF/MEK/MAPK phosphorylation, cyclin D1 expression, and cell proliferation. Further, cyclin D1 knockdown in HG-ESS dephosphorylates RB1 and inhibits proliferation. In keeping with these findings, we show that MEK and CDK4/6 inhibitors have anti-proliferative effects in HG-ESS, and combinations of these inhibitors have synergistic activity. These findings establish that YWHAE-NUTM2 regulates cyclin D1 expression and cell proliferation by dysregulating RAF/MEK/MAPK and Hippo/YAP-TAZ signaling pathways. Recent studies demonstrate Hippo/YAP-TAZ pathway aberrations in many sarcomas, but this is among the first studies to demonstrate a well-defined oncogenic mechanism as the cause of Hippo pathway dysregulation.

子宫内膜间质肉瘤（ESS）是继平滑肌肉瘤之后的第二种最常见的子宫间质癌亚型，许多ESS中都发现了致癌融合蛋白。我们以前的研究表明融合癌蛋白YWHAE-NUTM2在高度子宫内膜间质肉瘤（HG-ESS）中的转化特性和诊断意义，并表明cyclin D1是这些HG-ESS的诊断生物标志物。但是，尚未鉴定YWHAE–NUTM2的致癌机制及其在细胞周期蛋白D1表达中的作用。在当前的研究中，我们显示了HG-ESS中同时具有BRAF / RAF1和YAP / TAZ的YWHAE-NUTM2复合物。这些交互在功能上相关，因为YWHAE-NUTM2HG-ESS和其他模型的基因敲低会抑制RAF / MEK / MAPK磷酸化，细胞周期蛋白D1表达和细胞增殖。另外，HG-ESS中的细胞周期蛋白D1敲低使RB1去磷酸化并抑制增殖。与这些发现一致，我们表明MEK和CDK4 / 6抑制剂在HG-ESS中具有抗增殖作用，并且这些抑制剂的组合具有协同活性。这些发现证实，YWHAE-NUTM2通过失调RAF / MEK / MAPK和Hippo / YAP-TAZ信号通路来调节细胞周期蛋白D1的表达和细胞增殖。最近的研究表明许多肉瘤中的Hippo / YAP-TAZ途径畸变，但这是最早证明明确的致癌机制是Hippo途径失调的原因的研究之一。