Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase

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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

197 Citations (Scopus)


The Hippo signalling pathway plays important roles in animal development, physiology and tumorigenesis. 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.

Original languageEnglish
Pages (from-to)95-103
Number of pages9
JournalNature Cell Biology
Issue number1
Publication statusPublished - 1 Jan 2015
Externally publishedYes


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