The spliceosome is a therapeutic vulnerability in MYC-driven cancer.
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.
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.
Tiffany Y-T
TY
Hsu
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Lukas M
LM
Simon
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Nicholas J
NJ
Neill
Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C4, Canada.
Richard
R
Marcotte
Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C4, Canada.
Azin
A
Sayad
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Christopher S
CS
Bland
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.
Gloria V
GV
Echeverria
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Tingting
T
Sun
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Sarah J
SJ
Kurley
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Siddhartha
S
Tyagi
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Kristen L
KL
Karlin
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.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Rocio
R
Dominguez-Vidaña
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Jessica D
JD
Hartman
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Alexander
A
Renwick
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
Kathleen
K
Scorsone
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
Ronald J
RJ
Bernardi
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Physics, University of Illinois, Urbana, Illinois 61801, USA.
Samuel O
SO
Skinner
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Antrix
A
Jain
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Mayra
M
Orellana
Center for Chemical Biology, Bioscience Division, SRI International, Menlo Park, California 94025, USA.
Chandraiah
C
Lagisetti
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Physics, University of Illinois, Urbana, Illinois 61801, USA.
Ido
I
Golding
Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Sung Y
SY
Jung
Interdepartmental Program in Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Joel R
JR
Neilson
The Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Xiang H-F
XH
Zhang
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.
Thomas A
TA
Cooper
Center for Chemical Biology, Bioscience Division, SRI International, Menlo Park, California 94025, USA.
Thomas R
TR
Webb
Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C4, Canada.|Department of Medical Biophysics, University of Toronto, Toronto M5S 2J7, Canada.
Benjamin G
BG
Neel
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Chad A
CA
Shaw
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.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Thomas F
TF
Westbrook
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000096:biosynthesis / Q000235:genetics; D012326:RNA Splicing / Q000187:drug effects; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D017381:Spliceosomes / Q000187:drug effects* / Q000378:metabolism*; D000072668:Splicing Factor U2AF; D023041:Xenograft Model Antitumor Assays
C000602000:BUD31 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D012322:RNA Precursors; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D017413:Ribonucleoprotein, U2 Small Nuclear; D012261:Ribonucleoproteins; C112491:SF3B1 protein, human; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human