Gastric cancer is characteristic of poor prognosis and high death rate, making it the second most common cause of cancer-related death worldwide. Hippo pathway, as an emerging significant player in tumorigenesis, has recently been attracting increasing attention for the development of new anti-cancer drugs. In Hippo pathway, YAP can bind TEADs to form a “hybrid” transcription factor and therefore regulate growth-related genes. In contrast to targeting upstream regulators, inhibition of YAP, the ultimate downstream effector of Hippo signaling, may provide a more effective and direct way to redress the Hippo pathway. Jiao Shi and her colleagues from a research group led by Prof. Zhou Zhaocai at the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS identified VGLL4 as a clinical relevant natural antagonist of YAP, and importantly its TDU domain is sufficient for YAP inhibition by directly competing with YAP for binding TEADs. These findings combined with a 3D structural analysis of the VGLL4-TEAD complex, allowed for the development of a peptide-based YAP inhibitor. This peptide potently suppresses gastric tumor growth, providing an opportunity for treating gastric cancer which currently lacks effective treatment options. Moreover, cancer cells with an elevated ratio of YAP to VGLL4 appear to be more sensitive to this type of peptide treatment. Such therapeutic strategy may also be extended to other cancer types driven by hyperactive YAP. This study entitled “A Peptide Mimicking VGLL4 Function Acts as a YAP Antagonist Therapy against Gastric Cancer” was published online in Cancer Cell on Feb. 10, 2014. This work was done in collaboration with Prof. Zhang Lei and Prof. Ji Hongbin.