title: Complex interplay between β-catenin signalling and Notch effectors in intestinal tumorigenesis.
abstract: OBJECTIVE
  The activation of β-catenin signalling is a key step in intestinal tumorigenesis. Interplay between the β-catenin and Notch pathways during tumorigenesis has been reported, but the mechanisms involved and the role of Notch remain unclear.
  
  
  METHODS
  Notch status was analysed by studying expression of the Notch effector Hes1 and Notch ligands/receptors in human colorectal cancer (CRC) and mouse models of Apc mutation. A genetic approach was used, deleting the Apc and RBP-J or Atoh1 genes in murine intestine. CRC cell lines were used to analyse the control of Hes1 and Atoh1 by β-catenin signalling.
  
  
  RESULTS
  Notch signalling was found to be activated downstream from β-catenin. It was rapidly induced and maintained throughout tumorigenesis. Hes1 induction was mediated by β-catenin and resulted from both the induction of the Notch ligand/receptor and Notch-independent control of the Hes1 promoter by β-catenin. Surprisingly, the strong phenotype of unrestricted proliferation and impaired differentiation induced by acute Apc deletion in the intestine was not rescued by conditional Notch inactivation. Hyperactivation of β-catenin signalling overrode the forced differention induced by Notch inhibition, through the downregulation of Atoh1, a key secretory determinant factor downstream of Notch. This process involves glycogen synthase kinase 3 β (GSK3β) and proteasome-mediated degradation. The restoration of Atoh1 expression in CRC cell lines displaying β-catenin activation was sufficient to increase goblet cell differentiation, whereas genetic ablation of Atoh1 greatly increased tumour formation in Apc mutant mice.
  
  
  CONCLUSIONS
  Notch signalling is a downstream target of β-catenin hyperactivation in intestinal tumorigenesis. However, its inhibition had no tumour suppressor effect in the context of acute β-catenin activation probably due to the downregulation of Atoh1. This finding calls into question the use of γ-secretase inhibitors for the treatment of CRC and suggests that the restoration of Atoh1 expression in CRC should be considered as a therapeutic approach.
authors.affiliation: Department of Endocrinology, Metabolism and Cancer, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Peignon
authors.forename: Aurélie
authors.initials: A
authors.lastname: Durand
authors.forename: Wulfran
authors.initials: W
authors.lastname: Cacheux
authors.forename: Olivier
authors.initials: O
authors.lastname: Ayrault
authors.forename: Benoît
authors.initials: B
authors.lastname: Terris
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Noah F
authors.initials: NF
authors.lastname: Shroyer
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
authors.forename: Christine
authors.initials: C
authors.lastname: Perret
authors.forename: Béatrice
authors.initials: B
authors.lastname: Romagnolo
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D017491:Genes, APC; D052138:Genes, Neoplasm; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000072056:Transcription Factor HES-1; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051792:Basic Helix-Loop-Helix Proteins; D004273:DNA, Neoplasm; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009363:Neoplasm Proteins; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D051176:beta Catenin; C500942:ATOH1 protein, human; C497571:Rbpj protein, mouse; C078493:HES1 protein, human