An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth.
The spliceosome machinery is composed of multimeric protein complexes that generate a diverse repertoire of mRNA through coordinated splicing of heteronuclear RNAs. While somatic mutations in spliceosome components have been discovered in several cancer types, the molecular bases and consequences of spliceosome aberrations in cancer are poorly understood. Here we report for the first time that PRPF6, a member of the tri-snRNP (small ribonucleoprotein) spliceosome complex, drives cancer proliferation by preferential splicing of genes associated with growth regulation. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP spliceosome complexes, selectively abrogated growth in cancer cells with high tri-snRNP levels. High-resolution transcriptome analyses revealed that reduced PRPF6 alters the constitutive and alternative splicing of a discrete number of genes, including an oncogenic isoform of the ZAK kinase. These findings implicate an essential role for PRPF6 in cancer via splicing of distinct growth-related gene products.
Department of Pathology.
Adam S
AS
Adler
Department of Pathology.
Mark L
ML
McCleland
Department of Translational Oncology.
Sharon
S
Yee
Department of Pathology.
Murat
M
Yaylaoglu
Department of Pathology.
Sofia
S
Hussain
Department of Translational Oncology.
Ely
E
Cosino
Department of Protein Chemistry.
Gabriel
G
Quinones
Department of Molecular Biology.
Zora
Z
Modrusan
Department of Molecular Biology.
Somasekar
S
Seshagiri
Department of Biochemical and Cellular Pharmacology.
Eric
E
Torres
Department of Pathology.
Vivek S
VS
Chopra
Department of Molecular Biology.
Benjamin
B
Haley
Department of Bioinformatics, Genentech, Inc., South San Francisco, California 94080, USA;
Zemin
Z
Zhang
Department of Translational Oncology.
Elizabeth M
EM
Blackwood
Department of Molecular Biology.
Mallika
M
Singh
Department of Molecular Biology.
Melissa
M
Junttila
Department of Protein Chemistry.
Jean-Philippe
JP
Stephan
Department of Bioinformatics, Genentech, Inc., South San Francisco, California 94080, USA;
Jinfeng
J
Liu
Department of Bioinformatics, Genentech, Inc., South San Francisco, California 94080, USA;
Gregoire
G
Pau
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Eric R
ER
Fearon
Department of Bioinformatics, Genentech, Inc., South San Francisco, California 94080, USA;
Zhaoshi
Z
Jiang
Department of Pathology.
Ron
R
Firestein
D017398:Alternative Splicing; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D020033:Protein Isoforms; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D017381:Spliceosomes; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
C408605:PRPF6 protein, human; D020033:Protein Isoforms; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D014157:Transcription Factors
PRPF6; RNAi; colon cancer; spliceosome; tri-snRNP