TY - JOUR
T1 - SRSF1-Regulated Alternative Splicing in Breast Cancer
AU - Anczuków, Olga
AU - Akerman, Martin
AU - Cléry, Antoine
AU - Wu, Jie
AU - Shen, Chen
AU - Shirole, Nitin H.
AU - Raimer, Amanda
AU - Sun, Shuying
AU - Jensen, Mads A.
AU - Hua, Yimin
AU - Allain, Frédéric H.T.
AU - Krainer, Adrian R.
N1 - Funding Information:
We thank Chaolin Zhang for comments on the manuscript. We acknowledge assistance from the CSHL Microscopy and Sequencing Shared Resources, funded in part by NCI Cancer Center Support Grant 5P30CA045508. This work was supported by grants from the NCI (grants CA13106 to A.R.K. and CA178206 to O.A.) and from the NCCR RNA and Disease of the SNSF (to F.H.-T.A. and A.C.), and by postdoctoral awards to O.A. from the Susan B. Komen Foundation for the Cure (grant KG091029) and the Terri Brodeur Breast Cancer Foundation (grant 66810101). We acknowledge the use of data generated by TCGA, managed by NCI and NHGRI. M.A. is a founder and shareholder of Envisagenics, Inc., and A.R.K is a member of its scientific advisory board.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84952043621&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84952043621&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2015.09.005
DO - 10.1016/j.molcel.2015.09.005
M3 - Article
C2 - 26431027
AN - SCOPUS:84952043621
VL - 60
SP - 105
EP - 117
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 1
ER -