Letter | Published:

Synthetic lethality between Rb, p53 and Dicer or miR-17–92 in retinal progenitors suppresses retinoblastoma formation

Nature Cell Biology volume 14, pages 958965 (2012) | Download Citation

Abstract

Synthetic lethality is a promising strategy for specific targeting of cancer cells that carry mutations that are absent in normal cells1. This approach may help overcome the challenge associated with targeting dysfunctional tumour suppressors, such as p53 and Rb (refs 1, 2). Here we show that Dicer1 targeting prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of p53 and Rb. Although Dicer1 functions as a haploinsufficient tumour suppressor, its complete loss of function is selected against during tumorigenesis3,4,5. We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in the absence of p53. This synthetic lethality is mediated by the oncogenic miR-1792 cluster because its deletion phenocopies Dicer1 loss in this context. miR-17–92 inactivation suppresses retinoblastoma formation in mice and co-silencing of miR-17/20a and p53 cooperatively decreases the viability of human retinoblastoma cells. These data provide an explanation for the selective pressure against loss of Dicer1 during tumorigenesis and a proof-of-concept that targeting miRNAs may potentially represent a general approach for synthetic lethal targeting of cancer cells that harbour specific cancer-inducing genotypes.

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Acknowledgements

We thank O. Van Goethem, H. Stephan and M. Baumann for excellent technical advice and/or assistance. We thank M. Skipper for helpful comments on the manuscript and G. Hannon (Watson School of Biological Sciences, Cold Spring Harbor Laboratory, USA) for providing the Dicer1 floxed mice. This work was supported in part by FWO, the Belgian Foundation against Cancer (BFK), Geconcerteerde Onderzoek Aangelegenheden (GOA, KULeuven, Belgium) and the German Federal Ministry of Education and Research, BMBF (NGFNplus, ENGINE) as well as the EU (FP7, ONCOMIRS, Contract 201102). This publication reflects only the authors’ views. The commission is not liable for any use that may be made of the information herein.

Author information

Author notes

    • David Nittner
    •  & Irina Lambertz

    These authors contributed equally to this work

Affiliations

  1. Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, 3000 Leuven, Belgium

    • David Nittner
    • , Irina Lambertz
    • , Frederic Clermont
    • , Corinna Köhler
    •  & Jean-Christophe Marine
  2. Department of Molecular Biomedical Research, University of Ghent, B9000 Ghent, Belgium

    • David Nittner
    •  & Irina Lambertz
  3. Laboratory for Molecular Cancer Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium

    • David Nittner
    • , Frederic Clermont
    • , Corinna Köhler
    •  & Jean-Christophe Marine
  4. Center for Medical Genetics, Ghent University Hospital, B9000 Ghent, Belgium

    • Pieter Mestdagh
    • , Frank Speleman
    •  & Jo Vandesompele
  5. Exiqon A/S, Skelstedet 16, DK-2950 Vedbaek, Denmark

    • Søren Jensby Nielsen
  6. Department of Molecular Cell Biology, University Medical Centre, Leiden, The Netherlands

    • Aart Jochemsen
  7. Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Michael A. Dyer
  8. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

    • Michael A. Dyer
  9. Department of Pediatric Hematology and Oncology, University Children’s Hospital Essen, 45122 Essen, Germany

    • Alexander Schramm
    •  & Johannes H. Schulte

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Contributions

D.N. and I.L. performed experimental work, developed the hypothesis, analysed the data and coordinated the project. F.C. and C.K. performed the transfection studies in the human retinoblastoma cells and analysed the data. P.M. performed the miR-profiling experiments and analysed the data. S.J.N. contributed to the design of the miR-inhibition experiments. A.J. generated and characterized the Y79 p53KD cell line. A.S. and J.H.S. provided the human retinoblastoma samples. F.S., J.V., M.A.D., A.S. and J.H.S. discussed the hypothesis and contributed to data interpretation and experimental design. J-C.M. conceived the hypothesis, led the project, interpreted the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jean-Christophe Marine.

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DOI

https://doi.org/10.1038/ncb2556

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