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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Gene Expression Omnibus
RNA-seq data sets have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE66182.
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).
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Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms (2019)