PT  - JOURNAL ARTICLE
AU  - Tommaso Tabaglio
AU  - Diana HP Low
AU  - Winnie Koon Lay Teo
AU  - Pierre Alexis Goy
AU  - Piotr Cywoniuk
AU  - Heike Wollmann
AU  - Jessica Ho
AU  - Damien Tan
AU  - Joey Aw
AU  - Andrea Pavesi
AU  - Krzysztof Sobczak
AU  - Dave Keng Boon Wee
AU  - Ernesto Guccione
TI  - MBNL1 alternative splicing isoforms play opposing roles in cancer
AID  - 10.26508/lsa.201800157
DP  - 2018 Oct 01
TA  - Life Science Alliance
PG  - e201800157
VI  - 1
IP  - 5
4099  - https://www.life-science-alliance.org/content/1/5/e201800157.short
4100  - https://www.life-science-alliance.org/content/1/5/e201800157.full
SO  - Life Sci. Alliance2018 Oct 01; 1
AB  - 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.