Journal Article

Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase

Cheng, Hongcheng, Chen, Yan, Ma, Biao, Wu, Shian, Li, Jie, Liu, Jinhua, Mu, Chenglong, Cao, Lei, Chen, Quan, Zhou, Changqian, Zhu, Yushan, Chen, Ling, Gao, Ruize

2015

Overview

Wu and colleagues report that under hypoxic conditions the LATS2 kinase is targeted for degradation by the SIAH2 ubiquitin ligase, leading to inhibition of the Hippo kinase cascade and activation of YAP, which promotes tumour growth. The Hippo signalling pathway plays important roles in animal development, physiology and tumorigenesis 1 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/105 / 13/109 / 13/2 / 13/31 / 13/44 / 13/51 / 13/89 / 13/95 / 14/19 / 38/22 / 38/23 / 38/70 / 38/77 / 631/67 / 631/80/83/2360 / 631/80/86 / 64/60 / 82/29 / 82/80 / 82/83 / Adaptor Proteins, Signal Transducing - biosynthesis / Adaptor Proteins, Signal Transducing - metabolism / Analysis / Animals / Breast Neoplasms - genetics / Cancer Research / Cell Biology / Cell Hypoxia - physiology / Cell Line, Tumor / Cell Transformation, Neoplastic - genetics / Developmental Biology / Down-Regulation / Female / HEK293 Cells / HeLa Cells / Humans / Hypoxia / Hypoxia (Aquatic ecology) / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / letter / Life Sciences / Ligases / Mice / Mice, Nude / Neoplasm Transplantation / Nuclear Proteins - biosynthesis / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Phosphoproteins - biosynthesis / Phosphoproteins - metabolism / Phosphorylation / Physiological aspects / Protein-Serine-Threonine Kinases - biosynthesis / Protein-Serine-Threonine Kinases - metabolism / RNA Interference / RNA, Small Interfering / Signal Transduction / Stem Cells / Transcription Factors / Transplantation, Heterologous / Tumor Microenvironment / Tumor Suppressor Proteins - biosynthesis / Tumor Suppressor Proteins - metabolism / Ubiquitin / Ubiquitin-Protein Ligases - biosynthesis / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism