The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells
Open Access
- 2 September 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 33 (29), 3794-3802
- https://doi.org/10.1038/onc.2013.360
Abstract
Splicing abnormalities have profound impact in human cancer. Several splicing factors, including SAM68, have pro-oncogenic functions, and their increased expression often correlates with human cancer development and progression. Herein, we have identified using mass spectrometry proteins that interact with endogenous SAM68 in prostate cancer (PCa) cells. Among other interesting proteins, we have characterized the interaction of SAM68 with SND1, a transcriptional co-activator that binds spliceosome components, thus coupling transcription and splicing. We found that both SAM68 and SND1 are upregulated in PCa cells with respect to benign prostate cells. Upregulation of SND1 exerts a synergic effect with SAM68 on exon v5 inclusion in the CD44 mRNA. The effect of SND1 on CD44 splicing required SAM68, as it was compromised after knockdown of this protein or mutation of the SAM68-binding sites in the CD44 pre-mRNA. More generally, we found that SND1 promotes the inclusion of CD44 variable exons by recruiting SAM68 and spliceosomal components on CD44 pre-mRNA. Inclusion of the variable exons in CD44 correlates with increased proliferation, motility and invasiveness of cancer cells. Strikingly, we found that knockdown of SND1, or SAM68, reduced proliferation and migration of PCa cells. Thus, our findings strongly suggest that SND1 is a novel regulator of alternative splicing that promotes PCa cell growth and survival.Keywords
This publication has 61 references indexed in Scilit:
- Functional consequences of developmentally regulated alternative splicingNature Reviews Genetics, 2011
- Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinomaHepatology, 2011
- The splicing regulator Sam68 binds to a novel exonic splicing silencer and functions in SMN2 alternative splicing in spinal muscular atrophyThe EMBO Journal, 2010
- Rates of in situ transcription and splicing in large human genesNature Structural & Molecular Biology, 2009
- The Spliceosome: Design Principles of a Dynamic RNP MachineCell, 2009
- Alternative isoform regulation in human tissue transcriptomesNature, 2008
- The emerging role of splicing factors in cancerEMBO Reports, 2008
- Specific interaction between Sam68 and neuronal mRNAs: Implication for the activity‐dependent biosynthesis of elongation factor eEF1AJournal of Neuroscience Research, 2008
- The splicing factor SC35 has an active role in transcriptional elongationNature Structural & Molecular Biology, 2008
- Reversible cross-linking combined with immunoprecipitation to study RNA–protein interactions in vivoMethods, 2002