SRSF1-Regulated Alternative Splicing in Breast Cancer

Olga Anczuków, Martin Akerman, Antoine Cléry, Jie Wu, Chen Shen, Nitin H. Shirole, Amanda Raimer, Shuying Sun, Mads A. Jensen, Yimin Hua, Frédéric H.T. Allain, Adrian R. Krainer

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)105-117
Number of pages13
JournalMolecular cell
Volume60
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Anczuków, O., Akerman, M., Cléry, A., Wu, J., Shen, C., Shirole, N. H., Raimer, A., Sun, S., Jensen, M. A., Hua, Y., Allain, F. H. T., & Krainer, A. R. (2015). SRSF1-Regulated Alternative Splicing in Breast Cancer. Molecular cell, 60(1), 105-117. https://doi.org/10.1016/j.molcel.2015.09.005