RUNX3 is a novel negative regulator of oncogenic TEAD–YAP complex in gastric cancer

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Abstract

Runt-related transcription factor 3 (RUNX3) is a well-documented tumour suppressor that is frequently inactivated in gastric cancer. Here, we define a novel 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 strong oncogenic 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 RUNX3 at 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.

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Acknowledgements

This research is supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. The study was also supported by the Singapore National Research Foundation under its Translational and Clinical Research Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (Grants NMRC/TCR/001/2007 and NMRC/TCR/009-NUHS/2013). M Sudol was supported by seed grants from The NUS-Medical School, MBI and IMCB A*STAR. We are grateful to Professor Stefano Piccolo for providing us the 8xGTIIC-luciferase plasmid via Addgene. We also thank Professor Kunliang Guan for providing us myc-TEAD1 plasmid via Addgene. We acknowledge valuable comments on the manuscript from Dr Megan Finch-Edmondson.

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Qiao, Y., Lin, S., Chen, Y. et al. RUNX3 is a novel negative regulator of oncogenic TEAD–YAP complex in gastric cancer. Oncogene 35, 2664–2674 (2016). https://doi.org/10.1038/onc.2015.338

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