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RUNX3 is a Novel Negative Regulator of Oncogenic TEAD-YAP Complex in Gastric Cancer. (Oncogene, Sept 2015)

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.