Shanghai Tenth People's Hospital of Tongji University, School of Medicine and School of Life Science and Technology, Tongji University, Shanghai 200072, China.
Department of Hepatic Surgery, Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Cancer Cell. 2018 Jul 9;34(1):103-118.e9. doi: 10.1016/j.ccell.2018.06.002. Epub 2018 Jun 28.
YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A-mediated mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.
YAP 是 Hippo 通路的关键效应因子，通过从细胞质易位到细胞核来激活，以调节基因表达并促进肿瘤发生。虽然已经很好地研究了细胞质中抑制 YAP 的机制，但激活的 YAP 如何被隔离在核内仍然未知。在这里，我们证明 YAP 是一种核质穿梭蛋白，其核输出受 SET1A 介导的 YAP 在 K342 处的单甲基化控制，该修饰破坏了 YAP 与 CRM1 的结合。YAP 模拟甲基化敲入小鼠更容易发生结直肠肿瘤发生。临床上，YAP K342 甲基化与癌症存活率呈负相关。总之，我们的研究确定了 SET1A 介导的 K342 单甲基化作为调节 YAP 活性和肿瘤发生的重要调节机制。
