Guo Susu, Hu Xiaodi, Cotton Jennifer L, Ma Lifang, Li Qi, Cui Jiangtao, Wang Yongjie, Thakare Ritesh P, Tao Zhipeng, Ip Y Tony, Wu Xu, Wang Jiayi, Mao Junhao
Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States.
Elife. 2025 May 8;13:RP98386. doi: 10.7554/eLife.98386.
Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEADs. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, and , recently identified in human spindle cell rhabdomyosarcoma. We demonstrate that in contrast to VGLL2 and TEAD1 the fusion proteins are potent activators of TEAD-dependent transcription, and the function of these fusion proteins does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase EP300 to control TEAD-mediated transcriptional and epigenetic landscapes. We show that small-molecule EP300 inhibition can suppress fusion protein-induced oncogenic transformation both in vitro and in vivo in mouse models. Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying , , or translocations.
对Hippo信号通路调控肿瘤发生的研究主要集中在TEADs的转录共调节因子YAP和TAZ上。在此，我们提出了一种涉及VGLL和TEAD融合的致癌机制，该机制与Hippo信号通路相关，但不依赖YAP/TAZ。我们对最近在人类梭形细胞横纹肌肉瘤中发现的两种复发性融合体 和 进行了表征。我们证明，与VGLL2和TEAD1不同，融合蛋白是TEAD依赖性转录的有效激活剂，并且这些融合蛋白的功能不需要YAP/TAZ。此外，我们发现VGLL2和TEAD1融合体通过招募组蛋白乙酰转移酶EP300来参与特定的表观遗传调控，以控制TEAD介导的转录和表观遗传格局。我们表明，小分子EP300抑制在体外和小鼠模型体内均可抑制融合蛋白诱导的致癌转化。总体而言，我们的研究揭示了VGLL参与癌症的分子基础，并为靶向携带 、 或 易位的肿瘤提供了一个框架。
