Regulation of cellular quiescence by YAP/TAZ and Cyclin E1 in colon cancer cells: Implication in chemoresistance and cancer relapse
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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
Guillemette Huet, email: firstname.lastname@example.org
Keywords: c-Myc, CREB, stemness, liver metastases, prognosis
Received: May 20, 2016 Accepted: July 13, 2016 Published: August 04, 2016
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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