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The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer

Nature Genetics volume 48, pages 53–58 (2016)Cite this article

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Abstract

Small nucleolar RNAs (snoRNAs) are conserved noncoding RNAs best studied as ribonucleoprotein (RNP) guides in RNA modification1,2. To explore their role in cancer, we compared 5,473 tumor-normal genome pairs to identify snoRNAs with frequent copy number loss. The SNORD50A-SNORD50B snoRNA locus was deleted in 10–40% of 12 common cancers, where its loss was associated with reduced survival. A human protein microarray screen identified direct SNORD50A and SNORD50B RNA binding to K-Ras. Loss of SNORD50A and SNORD50B increased the amount of GTP-bound, active K-Ras and hyperactivated Ras-ERK1/ERK2 signaling. Loss of these snoRNAs also increased binding by farnesyltransferase to K-Ras and increased K-Ras prenylation, suggesting that KRAS mutation might synergize with SNORD50A and SNORD50B loss in cancer. In agreement with this hypothesis, CRISPR-mediated deletion of SNORD50A and SNORD50B in KRAS-mutant tumor cells enhanced tumorigenesis, and SNORD50A and SNORD50B deletion and oncogenic KRAS mutation co-occurred significantly in multiple human tumor types. SNORD50A and SNORD50B snoRNAs thus directly bind and inhibit K-Ras and are recurrently deleted in human cancer.

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Figure 1: Frequent deletion of SNORD50A/B in human cancers, SNORD50A/B expression and patient survival.
Figure 2: SNORD50A and SNORD50B directly bind K-Ras.
Figure 3: Impact of SNORD50A and SNORD50B loss on K-Ras.
Figure 4: Impact of SNORD50A and SNORD50B on K-Ras function.

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Acknowledgements

We thank J. Crabtree, J. Ferrell, S. Artandi, A. Oro, H. Chang and members of the Khavari laboratory for presubmission review and advice. This work was supported by the US Veterans Affairs Office of Research and Development and by US National Institutes of Health/National Cancer Institute grant CA142635 and by US National Institutes of Health/National Institute of Arthritis Musculoskeletal and Skin Diseases grant AR49737 to P.A.K.

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Authors and Affiliations

  1. Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA

    Zurab Siprashvili, Dan E Webster, Danielle Johnston, Rajani M Shenoy, Alexander J Ungewickell, Aparna Bhaduri, Ross Flockhart, Brian J Zarnegar, Yonglu Che & Paul A Khavari

  2. Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA

    Francesca Meschi & Joseph D Puglisi

  3. Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA

    Paul A Khavari

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  1. Zurab Siprashvili
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Contributions

Z.S. designed and executed experiments, analyzed data and wrote the manuscript. D.E.W., D.J., A.J.U., A.B., R.F., B.J.Z., Y.C. and F.M. executed experiments, analyzed data and contributed to design of experiments. D.J. and R.M.S. executed experiments. J.D.P. helped design experiments and analyzed data. P.A.K. designed experiments, analyzed data and wrote the manuscript.

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Correspondence to Paul A Khavari.

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Siprashvili, Z., Webster, D., Johnston, D. et al. The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer. Nat Genet 48, 53–58 (2016). https://doi.org/10.1038/ng.3452

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