Abstract
The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 3′ untranslated region (UTR) analysis upon miR-17-19b overexpression. We identify over one hundred miR-17-19b targets, of which 40% are co-regulated by c-MYC. Downregulation of a new miR-17/20 target, checkpoint kinase 2 (Chek2), increases the recruitment of HuR to c-MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 3′ UTR shortening at different stages of tumorigenesis.
Highlights
The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation
One way by which miRNAs confer robustness to the cell is through miRNA-mediated feed-forward loops (FFLs), whereby a transcription factor (TF) and a miRNA regulate the same set of protein-coding genes, with the miRNA being regulated by the same TF9,10
By applying an integrated approach centred on SILAC (Stable Isotope Labelling by Amino acids in Cell culture24)-based quantitative proteomics, transcriptomics and 30 untranslated region (UTR) analysis, we identify more than a hundred miR-17-19b targets
Summary
The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. One way by which miRNAs confer robustness to the cell is through miRNA-mediated feed-forward loops (FFLs), whereby a transcription factor (TF) and a miRNA regulate the same set of protein-coding genes, with the miRNA being regulated by the same TF9,10 An example of this regulatory circuit is offered by the interplay between the miR-17-92 cluster, the TF E2F1 and MYC9. Since MYC and E2F1 activate each other at the transcriptional level, there is the risk for the cell to enter a runaway positive feedback loop, resulting in excessively high levels of these transcriptional regulators Both factors induce the transcription of miR-17-92, which, in turn, negatively regulates E2F1 translation[11], acting as a break on this positive feedback loop. MiR-17 and miR-19 families are composed of pairs of miRNAs with identical seed regions: miR-17/miR-20a and miR-19a/miR-19b-112 As oncomirs, these miRNAs promote proliferation, inhibit apoptosis and induce tumour angiogenesis[13,14]. It has become widely accepted that miR-17-92 has the potential to act either as an oncogene or as a tumour suppressor, depending on the cellular context
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