Letter | Published:

Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase

Nature Cell Biology volume 17, pages 95103 (2015) | Download Citation

Abstract

The Hippo signalling pathway plays important roles in animal development, physiology and tumorigenesis1,2,3. Understanding how the activity of this pathway is regulated by the cellular microenvironment remains a major challenge. Here we elucidate a molecular mechanism by which hypoxia deactivates Hippo signalling. We demonstrate that the E3 ubiquitin ligase SIAH2 stimulates YAP by destabilizing LATS2, a critical component of the Hippo pathway, in response to hypoxia. Loss of SIAH2 suppresses tumorigenesis in a LATS2-dependent manner in a xenograft mouse model. We further show that YAP complexes with HIF1α and is essential for HIF1α stability and function in tumours in vivo. LATS2 is downregulated in human breast tumours and negatively correlates with SIAH2 expression levels, indicating that the SIAH2–LATS2 pathway may have a role in human cancer. Our data uncover oxygen availability as a microenvironment signal for the Hippo pathway and have implications for understanding the regulation of Hippo signalling in tumorigenesis.

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Acknowledgements

We thank H. Deng from Tsinghua University for Mass spectrometry analysis, Y. (YZ) Luo from Tsinghua University for providing the HRE–luciferase reporter plasmid and Y. (YG) Chen from Tsinghua University for providing the HA–VHL plasmid. We are deeply grateful to D. (DJ) Pan from Johns Hopkins University for his suggestions during the manuscript revision. This work was supported by the National Basic Research Program of China (2010CB912204, 2011CB9109903, 2011CB943903 and 2013CB531200) and the National Natural Sciences Foundation of China (31471319, 81130045 and 31171411).

Author information

Affiliations

  1. State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China

    • Biao Ma
    • , Yan Chen
    • , Ling Chen
    • , Hongcheng Cheng
    • , Chenglong Mu
    • , Jie Li
    • , Ruize Gao
    • , Changqian Zhou
    • , Lei Cao
    • , Jinhua Liu
    • , Yushan Zhu
    • , Quan Chen
    •  & Shian Wu
  2. State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

    • Quan Chen

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Contributions

B.M. conceived and designed the experiments with Y.Z., Q.C. and S.W. B.M. performed most of the experiments and data analysis in the laboratories of Q.C. and Y.Z. B.M., C.M. and R.G. performed xenograft implantation experiments. B.M. and C.M. performed studies on tissue microarrays of human patient samples. L. Chen, H.C. and J. Li contributed to cellular experiments and plasmid construction and protein purification. Y.C., L. Cao, C.Z. and J. Liu provided technical support. B.M. and S.W. wrote the manuscript with the help of all authors. Q.C. initiated, and supervised the project together with Y.Z. and S.W.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yushan Zhu or Quan Chen or Shian Wu.

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DOI

https://doi.org/10.1038/ncb3073

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