title: Regulation of cellular quiescence by YAP/TAZ and Cyclin E1 in colon cancer cells: Implication in chemoresistance and cancer relapse.
abstract: Our aim was to decipher the role and clinical relevance of the YAP/TAZ transcriptional coactivators in the regulation of the proliferation/quiescence balance in human colon cancer cells (CCC) and survival after 5FU-based chemotherapy. The prognostic value of YAP/TAZ on tumor relapse and overall survival was assessed in a five-year follow-up study using specimens of liver metastases (n = 70) from colon cancer patients. In 5FU-chemoresistant HT29-5F31 and -chemosensitive HCT116 and RKO CCC, a reversible G0 quiescent state mediated by Cyclin E1 down-regulation was induced by 5FU in 5F31 cells and recapitulated in CCC by either YAP/TAZ or Cyclin E1 siRNAs or the YAP inhibitor Verteporfin. Conversely, the constitutive active YAPdc-S127A mutant restricted cellular quiescence in 5FU-treated 5F31 cells and sustained high Cyclin E1 levels through CREB Ser-133 phosphorylation and activation. In colon cancer patients, high YAP/TAZ level in residual liver metastases correlated with the proliferation marker Ki-67 (p < 0.0001), high level of the YAP target CTGF (p = 0.01), shorter disease-free and overall survival (p = 0.008 and 0.04, respectively). By multivariate analysis and Cox regression model, the YAP/TAZ level was an independent factor of overall (Hazard ratio [CI 95%] 2.06 (1.02-4.16) p = 0.045) and disease-free survival (Hazard ratio [CI 95%] 1.98 (1.01-3.86) p = 0.045). Thus, YAP/ TAZ pathways contribute to the proliferation/quiescence switch during 5FU treatment according to the concerted regulation of Cyclin E1 and CREB. These findings provide a rationale for therapeutic interventions targeting these transcriptional regulators in patients with residual chemoresistant liver metastases expressing high YAP/TAZ levels.
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Corvaisier
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.
authors.forename: Marjolaine
authors.initials: M
authors.lastname: Bauzone
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.|Department of Digestive Surgery and Transplantation, CHRU Lille, F-59000, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Corfiotti
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.|Center of Biology-Pathology, CHRU Lille, F-59000, Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Renaud
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.|Department of Digestive Surgery and Transplantation, CHRU Lille, F-59000, Lille, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: El Amrani
authors.affiliation: UMR8576 CNRS-Université de Lille Nord de France, F-59658, Villeneuve d'Ascq, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Monté
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.|Department of Digestive Surgery and Transplantation, CHRU Lille, F-59000, Lille, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Truant
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.|Center of Biology-Pathology, CHRU Lille, F-59000, Lille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Leteurtre
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Formstecher
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
authors.affiliation: INSERM U938, "Molecular and Clinical Oncology", Hôpital Saint-Antoine, University Pierre et Marie Curie, F-75012, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Gespach
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.|Center of Biology-Pathology, CHRU Lille, F-59000, Lille, France.
authors.forename: Guillemette
authors.initials: G
authors.lastname: Huet
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000737:chemistry; D005500:Follow-Up Studies; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D015513:Oncogene Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011166:Porphyrins / Q000494:pharmacology; D011379:Prognosis; D016016:Proportional Hazards Models; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C475820:CCNE1 protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D019927:Cyclin E; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D015513:Oncogene Proteins; D010750:Phosphoproteins; D011166:Porphyrins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000077362:Verteporfin; D005472:Fluorouracil
keywords: CREB; c-Myc; liver metastases; prognosis; stemness