Article | Published:

Translation from unconventional 5′ start sites drives tumour initiation

Nature volume 541, pages 494499 (26 January 2017) | Download Citation

Abstract

We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs. An in vivo RNA interference screen of translational regulators revealed that depletion of conventional eIF2 complexes has adverse effects on normal but not oncogenic growth. Conversely, the alternative initiation factor eIF2A is essential for cancer progression, during which it mediates initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a role for the translation of 5′ untranslated regions in cancer, and expose new targets for therapeutic intervention.

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Acknowledgements

We thank J. Que for the R26-Sox2-IRES-eGFP mice, D. Xu and the Cornell Genomics Facility for sequencing support, the Rockefeller Proteomics Facility for protein/peptide analyses, members of the Fuchs’ laboratory for discussions, and L. Polak and M. Sribour for their support with tumorigenesis studies. We thank E. Heller for bioinformatics support, L. Calviello for support with RiboTaper, and F. Garcia-Quiroz and M. Jovanovic for critical reading of the manuscript. The Rockefeller University Proteomics Resource Center acknowledges funding from the Leona M. and Harry B. Helmsley Charitable Trust and Sohn Conferences Foundation for mass spectrometer instrumentation. The results published here are in part based upon data generated by the TCGA Research Network (http://cancergenome.nih.gov/). A.S. was supported by the Human Frontier Science Program Organization (HFSP, LT000639-2013) and is currently supported by the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7 under REA grant agreement no. 629861. S.N. is a Damon Runyon Fellow (DRG-2183-14). B.H. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM007739 to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. E.F. and J.S.W. are Investigators of the Howard Hughes Medical institute. This work was supported by grants to E.F. from the National Institutes of Health (R37-AR27883) and NYSTEM CO29559.

Author information

Author notes

    • Daniel Schramek

    Present address: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto M5G 1X5, Canada.

Affiliations

  1. Robin Chemers Neustein Laboratory of Mammalian Development and Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA

    • Ataman Sendoel
    • , Shruti Naik
    • , Nicholas C. Gomez
    • , Brian Hurwitz
    • , John Levorse
    • , Daniel Schramek
    •  & Elaine Fuchs
  2. Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA

    • Joshua G. Dunn
    • , Edwin H. Rodriguez
    •  & Jonathan S. Weissman
  3. Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA

    • Brian D. Dill
    •  & Henrik Molina

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Contributions

A.S. and E.F. conceived the project, designed the experiments and wrote the manuscript. A.S. and B.H. performed the experiments, and collected and analysed data. J.G.D., E.H.R., J.S.W. and N.C.G. contributed to ribosome profiling data analysis. D.S. contributed to control shRNA library generation and established HrasG12V; Tgfbr2-null cell lines. S.N. contributed to OPP experiments. J.L. carried out in utero lentiviral injections. H.M. and B.D.D. performed proteomics experiments and analysed proteomics data. E.F. supervised the project. All authors discussed the results and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Elaine Fuchs.

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    This file contains the raw data for Figures 4h and 5a,d.

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https://doi.org/10.1038/nature21036

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