The spliceosome is a therapeutic vulnerability in MYC-driven cancer

Nature. 2015 Sep 17;525(7569):384-8. doi: 10.1038/nature14985. Epub 2015 Sep 2.


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 programs. Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts. 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 properly. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, myc / genetics*
  • HeLa Cells
  • Humans
  • Introns / genetics
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis / drug therapy
  • Nuclear Proteins / metabolism
  • Phosphoproteins / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Precursors / biosynthesis
  • RNA Precursors / genetics
  • RNA Splicing / drug effects
  • RNA Splicing Factors
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Ribonucleoprotein, U2 Small Nuclear / metabolism
  • Ribonucleoproteins / metabolism
  • Spliceosomes / drug effects*
  • Spliceosomes / metabolism*
  • Splicing Factor U2AF
  • Xenograft Model Antitumor Assays


  • BUD31 protein, human
  • Nuclear Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins c-myc
  • RNA Precursors
  • RNA Splicing Factors
  • RNA, Messenger
  • Ribonucleoprotein, U2 Small Nuclear
  • Ribonucleoproteins
  • SF3B1 protein, human
  • Splicing Factor U2AF
  • U2AF1 protein, human

Associated data

  • GEO/GSE66182