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Widespread microRNA repression by Myc contributes to tumorigenesis

Abstract

The c-Myc oncogenic transcription factor (Myc) is pathologically activated in many human malignancies. Myc is known to directly upregulate a pro-tumorigenic group of microRNAs (miRNAs) known as the miR-17–92 cluster. Through the analysis of human and mouse models of B cell lymphoma, we show here that Myc regulates a much broader set of miRNAs than previously anticipated. Unexpectedly, the predominant consequence of activation of Myc is widespread repression of miRNA expression. Chromatin immunoprecipitation reveals that much of this repression is likely to be a direct result of Myc binding to miRNA promoters. We further show that enforced expression of repressed miRNAs diminishes the tumorigenic potential of lymphoma cells. These results demonstrate that extensive reprogramming of the miRNA transcriptome by Myc contributes to tumorigenesis.

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Figure 1: Repression of miRNA expression by Myc.
Figure 2: Myc associates with repressed pri-miRNA promoters.
Figure 3: Myc associates with conserved regions upstream of repressed miRNAs.
Figure 4: let-7 miRNAs are downregulated by Myc.
Figure 5: Myc binds to conserved regions upstream of let-7 miRNAs.
Figure 6: Expression of Myc-repressed miRNAs disadvantages lymphoma cell growth in vivo.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

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Acknowledgements

We thank D. Eick (GSF Research Centre, Munich) for P493-6 cells; S. Hammond and M. Thomson for assisting with miRNA arrays and for providing Burkitt's lymphoma miRNA expression data; and S. McMahon for advice and reagents for Myc knockdown experiments; and K. O'Donnell and members of the Mendell lab for critical reading of the manuscript. J.T.M. is a Rita Allen Foundation Scholar and receives support from the Lustgarten Foundation for Pancreatic Cancer Research. This work was also supported by grants from the National Institutes of Health (R01CA120185 to J.T.M., and R01CA122334 and R01CA102709 to A.T.-T.).

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T.-C.C., D.Y., A.T.-T. and J.T.M. designed the research; miRNA array experiments were performed by D.E.A., K.M.W., T.-C.C., D.Y., A.T.-T. and J.T.M.; RNA blotting experiments were performed by T.-C.C. and E.A.W.; ChIP experiments were performed by Y.-S.L. and T.-C.C.; retroviruses were constructed by T.-C.C.; tumorigenesis assays were performed by D.Y.; C.V.D. provided essential reagents and intellectual support; and T.-C.C. and J.T.M. wrote the manuscript.

Corresponding authors

Correspondence to Andrei Thomas-Tikhonenko or Joshua T Mendell.

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Chang, TC., Yu, D., Lee, YS. et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 40, 43–50 (2008). https://doi.org/10.1038/ng.2007.30

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