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.
Highlights
Cancer relapse after removal of the primary tumour and adjuvant therapy can occur after years or even decades of tumour remission
In order to establish a mechanistic link between entry into cellular quiescence and the YAP status in human colon cancer cells, we first examined the impact of YAP inhibition on cell cycle progression and clonogenic survival
Current therapeutic strategies directed against epithelial human solid tumors are mostly based on classical cytotoxic and genotoxic drugs, radiotherapeutic www.impactjournals.com/oncotarget interventions and newly designed anticancer agents targeting signaling and metabolic pathways
Summary
Cancer relapse after removal of the primary tumour and adjuvant therapy can occur after years or even decades of tumour remission. YAP and TAZ transcriptional activity is inhibited by the large tumor suppressor kinases (LATS1/2) that are phosphorylated and activated by the MST1/2 kinases, and a vast array of upstream endogenous and exogenous Hippo pathway regulators, including metabolic and nutrient signals, membrane receptors, E-cadherin -dependent cell-cell adhesion and hypoxia [6]. Phosphorylation of YAP at Ser-127 by LATS1/2 results in 14-3-3 binding, YAP cytoplasmic retention or degradation via YAP ubiquitination by the SCF (β-TRCP) E3 ubiquitin ligase [7] This Hippo pathway kinases cascade and upstream activators are considered as tumor suppressors acting through inhibitory signals on the YAP/ TAZ transcriptional co-activators [8,9,10,11]. Recent studies support a role of YAP/TAZ signaling in invasion [4] and chemoresistance to RAF and MEK inhibitors and other anticancer agents [23,24,25]
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