The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis.

河马途径在控制器官大小和组织动态平衡中至关重要，而放松调控会导致癌症。细胞外营养信号（例如葡萄糖）调节Hippo途径的激活。但是，机制仍不清楚。在这里，我们发现河马途径直接由己糖胺生物合成途径（HBP）调节，以响应代谢营养。从机制上讲，河马途径（YAP）的核心成分是在丝氨酸109处被O-GlcNAc转移酶（OGT）进行O-GlcNAcy酰化。并且此激活不依赖于AMPK。我们还确定OGT为YAP调控的基因，形成反馈环。最后，我们证实葡萄糖诱导的YAP O-GlcNAcylation和激活促进了肿瘤的发生。总之，我们的数据建立了HBP在直接将细胞外葡萄糖信号连接到Hippo-YAP途径和肿瘤发生中的分子机制和功能意义。