A splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation

Yangfan Qi, Jing Yu, Wei Han, Xiaojuan Fan, Haili Qian, Huanhuan Wei, Yi-hsuan S. Tsai, Jinyao Zhao, Wenjing Zhang, Quentin Liu, Songshu Meng, Yang Wang () and Zefeng Wang ()
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Yangfan Qi: Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University
Jing Yu: University of North Carolina at Chapel Hill
Wei Han: Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University
Xiaojuan Fan: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Haili Qian: State Key Lab of Molecular Oncology, Peking Union Medical College and Chinese Academy of Medical Sciences
Huanhuan Wei: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Yi-hsuan S. Tsai: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Jinyao Zhao: Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University
Wenjing Zhang: Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University
Quentin Liu: Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University
Songshu Meng: Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University
Yang Wang: Institute of Cancer Stem Cell, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University
Zefeng Wang: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Aberrant splicing is frequently found in cancer, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo–YAP signalling, a key pathway that regulates cell proliferation and organ size, is under control of a splicing switch. We show that TEAD4, the transcription factor that mediates Hippo–YAP signalling, undergoes alternative splicing facilitated by the tumour suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks an N-terminal DNA-binding domain, but maintains YAP interaction domain. TEAD4-S is located in both the nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumour growth in xenograft mouse models. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether, these data reveal a splicing switch that serves to fine tune the Hippo–YAP pathway.

Date: 2016
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DOI: 10.1038/ncomms11840

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