Publication Date:
2015-09-04
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hsu, Tiffany Y-T -- Simon, Lukas M -- Neill, Nicholas J -- Marcotte, Richard -- Sayad, Azin -- Bland, Christopher S -- Echeverria, Gloria V -- Sun, Tingting -- Kurley, Sarah J -- Tyagi, Siddhartha -- Karlin, Kristen L -- Dominguez-Vidana, Rocio -- Hartman, Jessica D -- Renwick, Alexander -- Scorsone, Kathleen -- Bernardi, Ronald J -- Skinner, Samuel O -- Jain, Antrix -- Orellana, Mayra -- Lagisetti, Chandraiah -- Golding, Ido -- Jung, Sung Y -- Neilson, Joel R -- Zhang, Xiang H-F -- Cooper, Thomas A -- Webb, Thomas R -- Neel, Benjamin G -- Shaw, Chad A -- Westbrook, Thomas F -- 1F30CA180447/CA/NCI NIH HHS/ -- 1R01CA178039-01/CA/NCI NIH HHS/ -- P30 AI036211/AI/NIAID NIH HHS/ -- P30CA125123/CA/NCI NIH HHS/ -- R01 AR045653/AR/NIAMS NIH HHS/ -- R01 AR060733/AR/NIAMS NIH HHS/ -- R01 CA140474/CA/NCI NIH HHS/ -- R01 HL045565/HL/NHLBI NIH HHS/ -- S10 RR024574/RR/NCRR NIH HHS/ -- U54-CA149196/CA/NCI NIH HHS/ -- England -- Nature. 2015 Sep 17;525(7569):384-8. doi: 10.1038/nature14985. Epub 2015 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Interdepartmental Program in Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, USA. ; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C4, Canada. ; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Physics, University of Illinois, Urbana, Illinois 61801, USA. ; Center for Chemical Biology, Bioscience Division, SRI International, Menlo Park, California 94025, USA. ; The Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Medical Biophysics, University of Toronto, Toronto M5S 2J7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26331541" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Breast Neoplasms/*drug therapy/*genetics/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/metabolism
;
RNA Precursors/biosynthesis/genetics
;
RNA Splicing/drug effects
;
RNA, Messenger/biosynthesis/genetics
;
Ribonucleoprotein, U2 Small Nuclear/metabolism
;
Ribonucleoproteins/metabolism
;
Spliceosomes/*drug effects/*metabolism
;
Xenograft Model Antitumor Assays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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