Qiao Y1, Lin SJ2, Chen Y1, Voon DC1, WZhu F3, Chuang LS1, Wang T1, Tan P1,2,4,5, Lee SC1,3, Yeoh KG6, Sudol M6,7,8, Ito Y1
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2 Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
3 Department of Haematology and Oncology, National University Cancer Institute, National University Health System, Singapore.
4 Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore.
5 Cellular and Molecular Research, National Cancer Centre, Singapore.
6 NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
7 Mechanobiology Institute (MBI), Singapore.
8 Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore.
Runt-related transcription factor 3 (RUNX3) is a well-documented tumour suppressor that is frequently inactivated in gastric cancer. Here, we define anovel mechanism by which RUNX3 exerts its tumour suppressor activity involving the TEAD-YAP complex, a potent positive regulator of proliferative genes. We report that the TEAD-YAP complex is not only frequently hyperactivated in liver and breast cancer, but also confers a strongoncogenic activity in gastric epithelial cells. The increased expression of TEAD-YAP in tumour tissues significantly correlates with poorer overall survival of gastric cancer patients. Strikingly, RUNX3 physically interacts with the N-terminal region of TEAD through its Runt domain. This interaction markedly reduces the DNA-binding ability of TEAD that attenuates the downstream signalling of TEAD-YAP complex. Mutation of RUNX3at Arginine 122 to Cysteine, which was previously identified in gastric cancer, impairs the interaction between RUNX3 and TEAD. Our data reveal that RUNX3 acts as a tumour suppressor by negatively regulating the TEAD-YAP oncogenic complex in gastric carcinogenesis. Oncogene advance online publication, 14 September 2015; doi:10.1038/onc.2015.338.