title: ZEB1-induced tumourigenesis requires senescence inhibition via activation of DKK1/mutant p53/Mdm2/CtBP and repression of macroH2A1.
abstract: Understand the role of ZEB1 in the tumour initiation and progression beyond inducing an epithelial-to-mesenchymal transition.
  
  
  
  Expression of the transcription factor ZEB1 associates with a worse prognosis in most cancers, including colorectal carcinomas (CRCs). The study uses survival analysis, in vivo mouse transgenic and xenograft models, gene expression arrays, immunostaining and gene and protein regulation assays.
  
  
  
  The poorer survival determined byZEB1in CRCs depended on simultaneous high levels of the Wnt antagonistDKK1, whose expression was transcriptionally activated by ZEB1. In cancer cells with mutantTP53, ZEB1 blocked the formation of senescence-associated heterochromatin foci at the onset of senescence by triggering a new regulatory cascade that involves the subsequent activation of DKK1, mutant p53, Mdm2 and CtBP to ultimately repress macroH2A1 (H2AFY). In a transgenic mouse model of colon cancer, partial downregulation ofZeb1was sufficient to induceH2afyand to trigger in vivo tumour senescence, thus resulting in reduced tumour load and improved survival. The capacity of ZEB1 to induce tumourigenesis in a xenograft mouse model requires the repression ofH2AFYby ZEB1. Lastly, the worst survival effect ofZEB1in patients with CRC ultimately depends on low expression ofH2AFYand of senescence-associated genes.
  
  
  
  The tumourigenic capacity of ZEB1 depends on its inhibition of cancer cell senescence through the activation of a herein identified new molecular pathway. These results set ZEB1 as a potential target in therapeutic strategies aimed at inducing senescence.
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: de Barrios
authors.affiliation: Lendület Cancer Biomarker Research Group, MTA TTK and 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.|Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Fernández-Aceñero
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Sánchez-Tilló
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Sánchez-Moral
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Siles
authors.affiliation: Lymphoma Group, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Esteve-Arenys
authors.affiliation: Lymphoma Group, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
authors.forename: Gaël
authors.initials: G
authors.lastname: Roué
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Casal
authors.affiliation: Department of Oral Immunology and Infectious Diseases and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Darling
authors.affiliation: Institute of Metabolic and Digestive Diseases, Hospital Clínic, Barcelona, Spain.|Gastrointestinal and Pancreatic Oncology Team, Biomedical Research Networking Centers in Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute (ISCIII), Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.|Gastrointestinal and Pancreatic Oncology Team, Biomedical Research Networking Centers in Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute (ISCIII), Barcelona, Spain.|Molecular Targets Program, James Graham Brown Cancer Center, Louisville, Kentucky, USA.|ICREA, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Postigo
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C501127:Dkk1 protein, mouse; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; C120756:macroH2A histone; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
keywords: COLORECTAL CARCINOMA