Question

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

Answer 1

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✨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.

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