Abstract

MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs1,2,3. Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts4,5,6,7. While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly8. Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

RNA-seq data sets have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE66182.

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Acknowledgements

We would like to thank J. Rosen, S. Butler, K. Neugebauer, M. Moore, S. Elledge, T. Davoli, members of T.F.W., C.A.S. and T.A.C. laboratories for comments, and P. Yu for bioinformatics support. The authors also acknowledge the joint participation by Adrienne Helis Melvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with Baylor College of Medicine for cancer research. The Dan L. Duncan Cancer Center Shared Resources was supported by the NCI P30CA125123 Center Grant and provided technical assistance including Cell-Based Assay Screening Service (D. Liu), Genomic and RNA Profiling Resource (L. White), Biostatistics & Informatics Shared Resource (S. Hilsenbeck), Cytometry and Cell Sorting (J. Sederstrom; P30 AI036211 and S10 RR024574), and the Proteomics and Metabolomics Core Facility (Cancer Prevention and Research Institute of Texas, RP12009). T.Y.-T.H. was supported by NIH pre-doctoral fellowship (NCI 1F30CA180447) and CPRIT training grant (RP101499). M.O. and R.J.B. were supported by The Gillson Longenbaugh Foundation. R.J.B. was supported by Alex’s Lemonade Stand Foundation. T.F.W. was supported by CPRIT (RP120583), the Susan G. Komen for the Cure (KG090355), the NIH (1R01CA178039-01 and U54- CA149196) and the DOD Breast Cancer Research Program (BC120604).

Author information

Author notes

    • Jessica D. Hartman

    Present address: Humacyte, Morrisville, North Carolina 27560, USA.

Affiliations

  1. Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA

    • Tiffany Y.-T. Hsu
    • , Nicholas J. Neill
    • , Christopher S. Bland
    • , Tingting Sun
    • , Sarah J. Kurley
    • , Siddhartha Tyagi
    • , Kristen L. Karlin
    • , Rocio Dominguez-Vidaña
    • , Samuel O. Skinner
    • , Antrix Jain
    • , Mayra Orellana
    • , Ido Golding
    • , Sung Y. Jung
    •  & Thomas F. Westbrook
  2. Interdepartmental Program in Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, USA

    • Tiffany Y.-T. Hsu
    • , Rocio Dominguez-Vidaña
    • , Joel R. Neilson
    •  & Thomas F. Westbrook
  3. Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA

    • Tiffany Y.-T. Hsu
  4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Tiffany Y.-T. Hsu
    • , Lukas M. Simon
    • , Nicholas J. Neill
    • , Christopher S. Bland
    • , Tingting Sun
    • , Sarah J. Kurley
    • , Siddhartha Tyagi
    • , Kristen L. Karlin
    • , Rocio Dominguez-Vidaña
    • , Jessica D. Hartman
    • , Alexander Renwick
    • , Mayra Orellana
    • , Chad A. Shaw
    •  & Thomas F. Westbrook
  5. Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C4, Canada

    • Richard Marcotte
    • , Azin Sayad
    •  & Benjamin G. Neel
  6. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Gloria V. Echeverria
    • , Joel R. Neilson
    •  & Thomas A. Cooper
  7. Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA

    • Gloria V. Echeverria
    •  & Thomas A. Cooper
  8. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA

    • Gloria V. Echeverria
    •  & Thomas A. Cooper
  9. Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Kathleen Scorsone
    •  & Ronald J. Bernardi
  10. Department of Physics, University of Illinois, Urbana, Illinois 61801, USA

    • Samuel O. Skinner
    •  & Ido Golding
  11. Center for Chemical Biology, Bioscience Division, SRI International, Menlo Park, California 94025, USA

    • Chandraiah Lagisetti
    •  & Thomas R. Webb
  12. The Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA

    • Xiang H.-F. Zhang
  13. Department of Medical Biophysics, University of Toronto, Toronto M5S 2J7, Canada

    • Benjamin G. Neel

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Contributions

T.Y.-T.H., N.J.N., R.M., C.S.B., G.V.E., T.S., S.J.K., S.T., K.L.K., J.D.H., K.S., R.J.B., S.O.S., A.J., C.L. and M.O. performed the experiments. L.M.S., A.S., R.D.-V., A.R. and C.A.S. performed statistical analyses. I.G., S.Y.J., J.R.N., X.H.-F.Z., T.A.C., T.R.W., B.G.N., C.A.S. and T.F.W. devised or supervised experiments. T.Y.-T.H. and T.F.W. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Thomas F. Westbrook.

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DOI

https://doi.org/10.1038/nature14985

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