An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth
- Adam S. Adler1,
- Mark L. McCleland1,
- Sharon Yee2,
- Murat Yaylaoglu1,
- Sofia Hussain1,
- Ely Cosino2,
- Gabriel Quinones3,
- Zora Modrusan4,
- Somasekar Seshagiri4,
- Eric Torres5,
- Vivek S. Chopra1,
- Benjamin Haley4,
- Zemin Zhang6,
- Elizabeth M. Blackwood2,
- Mallika Singh4,
- Melissa Junttila4,
- Jean-Philippe Stephan3,
- Jinfeng Liu6,
- Gregoire Pau6,
- Eric R. Fearon7,
- Zhaoshi Jiang6,8 and
- Ron Firestein1,8,9
- 1Department of Pathology,
- 2Department of Translational Oncology,
- 3Department of Protein Chemistry,
- 4Department of Molecular Biology,
- 5Department of Biochemical and Cellular Pharmacology,
- 6Department of Bioinformatics, Genentech, Inc., South San Francisco, California 94080, USA;
- 7Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
Abstract
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.
Keywords
Footnotes
↵8 These authors contributed equally to this work.
↵9 Corresponding author
E-mailronf{at}gene.com
Supplemental material is available for this article.
Article published online ahead of print. Article and publication date are online athttp://www.genesdev.org/cgi/doi/10.1101/gad.237206.113.
- ReceivedDecember 26, 2013.
- AcceptedApril 2, 2014.
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