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

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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)

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.

Suggested Citation

  • 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 & Zefeng Wang, 2016. "A splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11840
    DOI: 10.1038/ncomms11840
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