RT Journal Article SR Electronic T1 MBNL1 alternative splicing isoforms play opposing roles in cancer JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201800157 DO 10.26508/lsa.201800157 VO 1 IS 5 A1 Tommaso Tabaglio A1 Diana HP Low A1 Winnie Koon Lay Teo A1 Pierre Alexis Goy A1 Piotr Cywoniuk A1 Heike Wollmann A1 Jessica Ho A1 Damien Tan A1 Joey Aw A1 Andrea Pavesi A1 Krzysztof Sobczak A1 Dave Keng Boon Wee A1 Ernesto Guccione YR 2018 UL https://www.life-science-alliance.org/content/1/5/e201800157.abstract 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.