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VGLL4 targets a TCF4–TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer

Author

Listed:
  • Shi Jiao

    (State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Chuanchuan Li

    (State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Qian Hao

    (State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Haofei Miao

    (State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Lei Zhang

    (State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    The School of Life Science and Technology, ShanghaiTech University)

  • Lin Li

    (The School of Life Science and Technology, ShanghaiTech University
    State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Zhaocai Zhou

    (State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    The School of Life Science and Technology, ShanghaiTech University)

Abstract

Concerted co-regulation of multiple signalling pathways is crucial for tissue homoeostasis and tumorigenesis. Here we report that VGLL4, a previously identified YAP antagonist, also functions as a regulator of Wnt/β-catenin signalling. The expression of VGLL4 is significantly downregulated in clinical colorectal carcinoma (CRC) specimens, positively associated with patient survival rate, and inversely correlated with the expression of Wnt target genes in CRCs. Knockdown of VGLL4 enhances proliferation and tumour formation of CRC cells. A designed peptide mimicking the function of VGLL4 effectively inhibits CRC progression in a de novo mouse model. Mechanistically, TEAD4 associates with TCF4 to form a complex and cobind target genes. VGLL4 targets this TEAD4–TCF4 complex to interfere the functional interplay between TEAD4 and TCF4, suppressing the transactivation of TCF4. Collectively, our study indicates that Wnt/β-catenin and Hippo-YAP signalling are directly linked at transcription factor-level, and VGLL4 can target a TEAD4–TCF4 complex to co-regulate both pathways.

Suggested Citation

  • Shi Jiao & Chuanchuan Li & Qian Hao & Haofei Miao & Lei Zhang & Lin Li & Zhaocai Zhou, 2017. "VGLL4 targets a TCF4–TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14058
    DOI: 10.1038/ncomms14058
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    Cited by:

    1. Zhiyun Ren & Yilin Zhao & Wentao Yu & Xia Zhang & Xiaoxuan Song & Yanling Bao & Meng Hu & Lishuang Chen & Hao Yang & Bingkai Cheng & Cong Liu & Yunyun Jin & Lei Zhang & Bo Sun, 2026. "VGLL4-driven TEAD4 multimerization orchestrates DNA binding and YAP recruitment," Nature Communications, Nature, vol. 17(1), pages 1-16, December.
    2. Yang Sun & Lu Hu & Zhipeng Tao & Gopala K. Jarugumilli & Hannah Erb & Alka Singh & Qi Li & Jennifer L. Cotton & Patricia Greninger & Regina K. Egan & Y. Tony Ip & Cyril H. Benes & Jianwei Che & Junhao, 2022. "Pharmacological blockade of TEAD–YAP reveals its therapeutic limitation in cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Jinlong Suo & Duo Wang & Jinghui Wang & Xubin Yin & Xuye Hu & Rui Shao & Shuqin Chen & Shaokun Sun & Jingyi Feng & Lijun Wang & Heng Feng & Zhengda Li & Wulei Hou & Lei Zhang & Yong Chen & Xianyou Zhe, 2025. "Targeting VGLL4 maintains extracellular matrix homeostasis and mitigates osteoarthritis in a preclinical model," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    4. Yuegui Guo & Zhehui Zhu & Zhenyu Huang & Long Cui & Wei Yu & Wanjin Hong & Zhaocai Zhou & Peng Du & Chen-Ying Liu, 2022. "CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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