Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism

// Zeina Bash-Imam 1 * , Gabriel Thérizols 1 * , Anne Vincent 1 , Florian Lafôrets 1 , Micaela Polay Espinoza 1 , Nathalie Pion 1 , Françoise Macari 4 , Julie Pannequin 4 , Alexandre David 4 , Jean-Christophe Saurin 1 , Hichem C. Mertani 1 , Julien Textoris 3 , Didier Auboeuf 1 , Frédéric Catez 1 , Nicole Dalla Venezia 1 , Martin Dutertre 2 ** , Virginie Marcel 1 ** and Jean-Jacques Diaz 1 ** 1 Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, F-69373 Lyon, France 2 Institut Curie, CNRS UMR 3348, Centre Universitaire, F-91405 Orsay, France 3 EA7426, Université Lyon 1, Hospices Civils de Lyon, bioMérieux S.A. Pathophysiology of injury-induced immunosuppression (PI3), F69003 Lyon, France 4 IGF, CNRS, INSERM, Université Montpellier, F-34094 Montpellier, France * These authors have equally contributed to this work ** Senior authors have equally contributed to this work Correspondence to: Jean-Jacques Diaz, email: jean-jacques.diaz@lyon.unicancer.fr Keywords: 5-fluorouracil, translation, translatome profiling, miRNA, colorectal cancer Received: February 24, 2017 Accepted: April 06, 2017 Published: May 03, 2017 ABSTRACT 5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug in colorectal cancer. Previous studies showed that 5-FU modulates RNA metabolism and mRNA expression. In addition, it has been reported that 5-FU incorporates into the RNAs constituting the translational machinery and that 5-FU affects the amount of some mRNAs associated with ribosomes. However, the impact of 5-FU on translational regulation remains unclear. Using translatome profiling, we report that a clinically relevant dose of 5-FU induces a translational reprogramming in colorectal cancer cell lines. Comparison of mRNA distribution between polysomal and non-polysomal fractions in response to 5-FU treatment using microarray quantification identified 313 genes whose translation was selectively regulated. These regulations were mostly stimulatory (91%). Among these genes, we showed that 5-FU increases the mRNA translation of HIVEP2 , which encodes a transcription factor whose translation in normal condition is known to be inhibited by mir-155. In response to 5-FU, the expression of mir-155 decreases thus stimulating the translation of HIVEP2 mRNA. Interestingly, the 5-FU-induced increase in specific mRNA translation was associated with reduction of global protein synthesis. Altogether, these findings indicate that 5-FU promotes a translational reprogramming leading to the increased translation of a subset of mRNAs that involves at least for some of them, miRNA-dependent mechanisms. This study supports a still poorly evaluated role of translational control in drug response.