TY - JOUR
T1 - MiR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth
AU - Mihailovich, Marija
AU - Bremang, Michael
AU - Spadotto, Valeria
AU - Musiani, Daniele
AU - Vitale, Elena
AU - Varano, Gabriele
AU - Zambelli, Federico
AU - Mancuso, Francesco M.
AU - Cairns, David A.
AU - Pavesi, Giulio
AU - Casola, Stefano
AU - Bonaldi, Tiziana
PY - 2015/11/10
Y1 - 2015/11/10
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms9725
DO - 10.1038/ncomms9725
M3 - Article
AN - SCOPUS:84946910965
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 8725
ER -