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Myc overexpression brings out unexpected antiapoptotic effects of miR-34a

Oncogene volume 30, pages 2587–2594 (2011)Cite this article

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Abstract

Downregulation of microRNA-34a by Myc is known to be essential for tumorigenesis and improve tumor-cell survival. Conversely, upregulation of miR-34a by p53 is thought to enhance its acetylation and activity and contribute to the pro-apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR-34a levels in B-lymphoid cells with Myc overexpression would aid therapeutic apoptosis. Unexpectedly, delivery of miR-34a, which doesn't target p53 directly, severely compromised steady-state p53 levels. This effect was preceded and mediated by direct targeting of Myc, which sustained p53 protein levels via the Arf–Hdm2 pathway. As a result, in the presence of Myc, miR-34a inhibited p53-dependent bortezomib-induced apoptosis as efficiently as anti-p53 small interfering RNA. Conversely, inhibition of miR-34a using antisense RNA sensitized lymphoma cells to therapeutic apoptosis. Thus, in tumors with deregulated Myc expression, miR-34a confers drug resistance and could be considered a therapeutic target.

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Acknowledgements

We thank Drs Joshua Mendell and Tsung-Cheng Chang (Johns Hopkins University) for sharing unpublished data on miR-34a function in B-cells. Current and past members of our laboratories (in particular Drs Duonan Yu, James Psathas, Michael Dews and Elaine Chung) are acknowledged for many stimulating discussions. We are grateful to the Rosetta Gene Expression Laboratory for performing microarray hybridization experiments and Miho Kibukawa (Merck & Co., Inc.)—for technical support. We thank Dr Dirk Eick (GSF Research Centre, Munich) for P493-6 cells, Dr Carlo Croce (Ohio State University, Columbus) for GM607 cells and Dr Joelle Wiels (Institut Gustave Roussy, Villejuif, France) for Ly47cells. This work was supported by US National Institutes of Health grant CA 122334 to ATT and the Institutional Development Fund of the Children's Hospital of Philadelphia (ATT), as well as NIH grants R01CA098172-07, R21CA152786-01 and R01CA090465-08 to SBM.

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  1. J M Schelter & M A Cleary

    Present address: 6Current address: Department of Automated Biotechnology, Merck & Co., Inc., 502 Louise Lane, North Wales, PA 19454, USA.,

Authors and Affiliations

  1. Division of Cancer Pathobiology, Department of Pathology & Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

    E Sotillo & A Thomas-Tikhonenko

  2. NIH/Merck Summer Program, University of Pennsylvania, Philadelphia, PA, USA

    T Laver & A Thomas-Tikhonenko

  3. Cancer Biology/CAMB Graduate Program, University of Pennsylvania, Philadelphia, PA, USA

    H Mellert, S McMahon & A Thomas-Tikhonenko

  4. Rosetta Inpharmatics, Seattle, WA, USA

    J M Schelter & M A Cleary

  5. Department of Cancer Biology, Thomas Jefferson Medical College, Philadelphia, PA, USA

    S McMahon

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Correspondence to A Thomas-Tikhonenko.

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Michele Cleary is an employee of Merck Inc. The authors declare no further competing financial interests.

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Sotillo, E., Laver, T., Mellert, H. et al. Myc overexpression brings out unexpected antiapoptotic effects of miR-34a. Oncogene 30, 2587–2594 (2011). https://doi.org/10.1038/onc.2010.634

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