YAP drives proliferation and tumorigenesis by recruiting Mediator to super- enhancer elements (H69)

The Hippo/YAP signaling pathway is a crucial regulator of tissue growth and stem cell activity. YAP is also a powerful driver of tumor growth and its nuclear accumulation is frequently observed in human cancer.However, the molecular mechanism employed by YAP to orchestrate transcriptional outputs are undefined. Here, we utilize genomic technologies to demonstrate that YAP occupancy is restricted to a small number of distal regulatory elements highly enriched for superenhancers.Target genes associated with these elements are selectively sensitive to the loss of YAP in cancer cells. YAP directs recruitment of the Mediator complex to activate transcriptional regulation from these enhancers without affecting chromatin organizationWe also provide in vivo genetic evidence that loss of Mediator rescues YAP-driven cancer cell proliferation and organ overgrowth. Our data provide a molecular mechanism behind YAP-driven tumorigenesis, and highlights transcriptional control as a potential therapeutic strategy for YAP-driven cancers.

Hippo/YAP信号通路是调控组织生长与干细胞活性的关键通路。YAP亦是驱动肿瘤生长的强效因子，其核积累现象在人类癌症中较为常见。然而，YAP介导转录调控输出的分子机制尚未明确。本研究借助基因组学技术证实，YAP的结合位点仅局限于少量远端调控元件，且这些元件显著富集于超级增强子（superenhancer）区域。与这些调控元件相关的靶基因，在癌细胞中对YAP缺失呈现出选择性敏感性。YAP可介导中介体复合物（Mediator complex）的招募，以激活这些增强子的转录调控，且不影响染色质组织结构。本研究还提供了体内遗传学证据，表明中介体复合物的缺失可挽救YAP驱动的癌细胞增殖与器官过度生长。本研究数据阐明了YAP驱动肿瘤发生的分子机制，并指出转录调控可作为YAP相关性癌症的潜在治疗策略。