Oncotarget

Research Papers:

Regulation of cellular quiescence by YAP/TAZ and Cyclin E1 in colon cancer cells: Implication in chemoresistance and cancer relapse

Matthieu Corvaisier, Marjolaine Bauzone, François Corfiotti, Florence Renaud, Mehdi El Amrani, Didier Monté, Stéphanie Truant, Emmanuelle Leteurtre, Pierre Formstecher, Isabelle Van Seuningen, Christian Gespach and Guillemette Huet _

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Oncotarget. 2016; 7:56699-56712. https://doi.org/10.18632/oncotarget.11057

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Abstract

Matthieu Corvaisier1, Marjolaine Bauzone1, François Corfiotti1,2, Florence Renaud1,3, Mehdi El Amrani1,2, Didier Monté4, Stéphanie Truant1,2, Emmanuelle Leteurtre1,3, Pierre Formstecher1, Isabelle Van Seuningen1, Christian Gespach5,*, Guillemette Huet1,3,*

1University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France

2Department of Digestive Surgery and Transplantation, CHRU Lille, F-59000, Lille, France

3Center of Biology-Pathology, CHRU Lille, F-59000, Lille, France

4UMR8576 CNRS-Université de Lille Nord de France, F-59658, Villeneuve d'Ascq, France

5INSERM U938, “Molecular and Clinical Oncology”, Hôpital Saint-Antoine, University Pierre et Marie Curie, F-75012, Paris, France

*These authors contributed equally to this work

Correspondence to:

Guillemette Huet, email: guillemette.huet@inserm.fr

Keywords: c-Myc, CREB, stemness, liver metastases, prognosis

Received: May 20, 2016     Accepted: July 13, 2016     Published: August 04, 2016

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.


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