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

doi:10.1038/ncb3073

Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase

Nat Cell Biol. 2015 Jan;17(1):95-103. doi: 10.1038/ncb3073. Epub 2014 Dec 1.

Authors

Biao Ma¹, Yan Chen¹, Ling Chen¹, Hongcheng Cheng¹, Chenglong Mu¹, Jie Li¹, Ruize Gao¹, Changqian Zhou¹, Lei Cao¹, Jinhua Liu¹, Yushan Zhu¹, Quan Chen², Shian Wu¹

Affiliations

¹ State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
² 1] State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China [2] State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

PMID: 25438054
DOI: 10.1038/ncb3073

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / biosynthesis
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Breast Neoplasms / genetics
Cell Hypoxia / physiology*
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Down-Regulation
Female
HEK293 Cells
HeLa Cells
Hippo Signaling Pathway
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Mice
Mice, Nude
Neoplasm Transplantation
Nuclear Proteins / biosynthesis
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Phosphoproteins / biosynthesis
Phosphoproteins / metabolism*
Phosphorylation
Protein Serine-Threonine Kinases / biosynthesis
Protein Serine-Threonine Kinases / metabolism*
RNA Interference
RNA, Small Interfering
Signal Transduction
Transcription Factors
Transplantation, Heterologous
Tumor Microenvironment
Tumor Suppressor Proteins / biosynthesis
Tumor Suppressor Proteins / metabolism*
Ubiquitin-Protein Ligases / biosynthesis
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Nuclear Proteins
Phosphoproteins
RNA, Small Interfering
Transcription Factors
Tumor Suppressor Proteins
YAP-Signaling Proteins
YAP1 protein, human
Ubiquitin-Protein Ligases
seven in absentia proteins
LATS2 protein, human
Protein Serine-Threonine Kinases