title: Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase.
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.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Hongcheng
authors.initials: H
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Mu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Ruize
authors.initials: R
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Changqian
authors.initials: C
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Shian
authors.initials: S
authors.lastname: Wu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014157:Transcription Factors; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D000098563:Seven in Absentia Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases