Molecular Cell
Volume 60, Issue 1, 1 October 2015, Pages 105-117
Journal home page for Molecular Cell

Article
SRSF1-Regulated Alternative Splicing in Breast Cancer

https://doi.org/10.1016/j.molcel.2015.09.005Get rights and content
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Highlights

  • Developed a tool for splicing detection and quantification in RNA-seq data

  • Identified and validated hundreds of endogenous SRSF1-regulated splicing targets

  • Defined regulatory maps to predict the positional effects of SRSF1 binding

  • Identified oncogenic SRSF1-regulated splicing targets in human tumors

Summary

Splicing factor SRSF1 is upregulated in human breast tumors, and its overexpression promotes transformation of mammary cells. Using RNA-seq, we identified SRSF1-regulated alternative splicing (AS) targets in organotypic three-dimensional MCF-10A cell cultures that mimic a context relevant to breast cancer. We identified and validated hundreds of endogenous SRSF1-regulated AS events. De novo discovery of the SRSF1 binding motif reconciled discrepancies in previous motif analyses. Using a Bayesian model, we determined positional effects of SRSF1 binding on cassette exons: binding close to the 5′ splice site generally promoted exon inclusion, whereas binding near the 3′ splice site promoted either exon skipping or inclusion. Finally, we identified SRSF1-regulated AS events deregulated in human tumors; overexpressing one such isoform, exon-9-included CASC4, increased acinar size and proliferation, and decreased apoptosis, partially recapitulating SRSF1’s oncogenic effects. Thus, we uncovered SRSF1 positive and negative regulatory mechanisms, and oncogenic AS events that represent potential targets for therapeutics development.

Cited by (0)

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Co-first author

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Present address: Envisagenics, Inc., Huntington, NY 11743, USA

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Present address: Massachusetts Institute of Technology, Cambridge, MA 02139, USA

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Present address: University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

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Present address: University of California, San Diego, La Jolla, CA 92093, USA

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Present address: Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark

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Present address: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China