Splicing factors control triple-negative breast cancer cell mitosis through SUN2 interaction and sororin intron retention

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic opportunities. Recently, splicing factors have gained attention as potential targets for cancer treatment. We performed an RNAi screen targeting 244 individual splicing factors to systematically evaluate their role in TNBC cell proliferation. We identified nine splicing factors, including SNRPD2, SNRPD3 and NHP2L1, of which depletion inhibited proliferation in two TNBC cell lines by deregulation of sister chromatid cohesion (SCC) via increased sororin intron 1 retention and down-regulation of SMC1, MAU2 and ESPL1. Protein-protein interaction analysis of SNRPD2, SNRPD3 and NHP2L1 identified that seven out of the nine identified splicing factors belong to the same spliceosome complex including novel componentSUN2 that was also critical for efficient sororin splicing. Finally, sororin transcript levels are highly correlated to various proliferation markers in BC patients, suggesting that deregulating sororin levels through targeting of the relevant splicing factors might be a potential strategy to treat TNBC