title: ASPP2 controls epithelial plasticity and inhibits metastasis through β-catenin-dependent regulation of ZEB1.
abstract: Epithelial to mesenchymal transition (EMT), and the reverse mesenchymal to epithelial transition (MET), are known examples of epithelial plasticity that are important in kidney development and cancer metastasis. Here we identify ASPP2, a haploinsufficient tumour suppressor, p53 activator and PAR3 binding partner, as a molecular switch of MET and EMT. ASPP2 contributes to MET in mouse kidney in vivo. Mechanistically, ASPP2 induces MET through its PAR3-binding amino-terminus, independently of p53 binding. ASPP2 prevents β-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting β-catenin's N-terminal phosphorylation to stabilize the β-catenin-E-cadherin complex. ASPP2 limits the pro-invasive property of oncogenic RAS and inhibits tumour metastasis in vivo. Reduced ASPP2 expression results in EMT, and is associated with poor survival in hepatocellular carcinoma and breast cancer patients. Hence, ASPP2 is a key regulator of epithelial plasticity that connects cell polarity to the suppression of WNT signalling, EMT and tumour metastasis.
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] International Joint Cancer Institute &Eastern Hospital of Hepatobiliary Surgery, The Second Military Medical University, Shanghai 200433, China [2] PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, 28 Fuxing Road Beijing 100853, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Bu
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Christophe
authors.initials: C
authors.lastname: Royer
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Serres
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Larkin
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Manuel Sarmiento
authors.initials: MS
authors.lastname: Soto
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Salter
authors.affiliation: 1] Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK [2] Institute of Surgical Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Fritzsche
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Casmir
authors.initials: C
authors.lastname: Turnquist
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: Koch
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Zak
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Guangxi Cancer Hospital, Guangxi Medical University, Guangxi 530021, China.
authors.forename: Guobin
authors.initials: G
authors.lastname: Wu
authors.affiliation: Guangxi Cancer Hospital, Guangxi Medical University, Guangxi 530021, China.
authors.forename: Anmin
authors.initials: A
authors.lastname: Liang
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Olofsen
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Hancock
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.affiliation: Centre for Pathology, St Mary's Hospital, Imperial College, London W2 1NY, UK.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Goldin
authors.affiliation: 1] International Joint Cancer Institute &Eastern Hospital of Hepatobiliary Surgery, The Second Military Medical University, Shanghai 200433, China [2] PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, 28 Fuxing Road Beijing 100853, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: 1] International Joint Cancer Institute &Eastern Hospital of Hepatobiliary Surgery, The Second Military Medical University, Shanghai 200433, China [2] PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, 28 Fuxing Road Beijing 100853, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: 1] International Joint Cancer Institute &Eastern Hospital of Hepatobiliary Surgery, The Second Military Medical University, Shanghai 200433, China [2] PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, 28 Fuxing Road Beijing 100853, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C090468:TP53BP2 protein, human; D014157:Transcription Factors; C511437:Trp53bp2 protein, mouse; D025521:Tumor Suppressor Proteins; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin