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Life Sci Alliance. 2018 Sep 7;1(5):e201800157. doi: 10.26508/lsa.201800157. eCollection 2018 Oct.

MBNL1 alternative splicing isoforms play opposing roles in cancer.

Author information

1
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.
2
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3
Cancer Science Institute, Singapore.
4
Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Poznan, Poland.
5
Institute of High Performance Computing, Agency for Science, Technology and Research, Singapore.
6
Bioinformatics Institute, Agency for Science, Technology and Research, Singapore.
7
National Cancer Centre Singapore, Singapore.
8
Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Abstract

The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 Δex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 Δex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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