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Mol Cancer Res. 2019 Sep;17(9):1920-1930. doi: 10.1158/1541-7786.MCR-18-1291. Epub 2019 May 28.

Serine/Arginine-Rich Splicing Factor 3 Modulates the Alternative Splicing of Cytoplasmic Polyadenylation Element Binding Protein 2.

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Department of Biochemistry and Molecular Biology, Virginia Commonwealth University (VCU), Richmond Virginia.
Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, Florida.
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University (VCU), Richmond Virginia.
VCU Massey Cancer Center, Cancer Cell Signaling Program, VCU, Richmond Virginia.
Research Service, Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia.
VCU Institute of Molecular Medicine, Richmond, Virginia.
VCU Johnson Center for Critical Care and Pulmonary Research, Richmond, Virginia.
Research Service, James A. Haley Veterans Hospital, Tampa, Florida.
The Moffitt Cancer Center, Tampa, Florida.
Contributed equally


Triple negative breast cancer (TNBC) has an unusually low 5-year survival rate linked to higher metastatic rates. Our laboratory recently delineated a role for the alternative RNA splicing (AS) of cytoplasmic polyadenylation element binding protein 2 (CPEB2), via inclusion/exclusion of exon 4, in the metastasis of TNBC. In these studies, the mechanism governing the inclusion/exclusion of exon 4 was examined. Specifically, the RNA trans-factor, SRSF3, was found to be explicitly associated with CPEB2 exon 4. A SRSF3 consensus sequence was identified in exon 4, and mutation of this sequence abolished the association of SRSF3. The expression of SRSF3 was upregulated in TNBC cells upon the acquisition of anoikis resistance correlating with a reduction in the CPEB2A/B ratio. Importantly, downregulation of SRSF3 in these cells by siRNA induced the exclusion of exon 4 in cells increasing the ratio of CPEB2A (exon 4 excluded) to CPEB2B (exon 4 included). Downregulation of SRSF3 also reversed the CPEB2A/B ratio of a wild-type CPEB2 exon 4 minigene and endogenous CPEB2 pre-mRNA, but not a mutant CPEB2 minigene with the SRSF3 RNA cis-element ablated. SRSF3 downregulation ablated the anoikis resistance of TNBC cells, which was "rescued" by ectopic expression of CPEB2B. Finally, analysis of The Cancer Genome Atlas database showed a positive relationship between SRSF3 expression and lower CPEB2A/B ratios in aggressive breast cancers. IMPLICATIONS: These findings demonstrate that SRSF3 modulates CPEB2 AS to induce the expression of the CPEB2B isoform that drives TNBC phenotypes correlating with aggressive human breast cancer. VISUAL OVERVIEW:

[Available on 2020-09-01]

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