Splicing factor BUD31 promotes ovarian cancer progression through sustaining the expression of anti-apoptotic BCL2L12

Abstract

Dysregulated expression of splicing factors has important roles in cancer development and progression. However, it remains a challenge to identify the cancer-specific splicing variants. Here we demonstrated that spliceosome component BUD31 is increased in ovarian cancer, and its higher expression predicts worse prognosis. We characterized the BUD31 binding motif and found that BUD31 preferentially binds exon-intron regions near splicing sites by CLIP-seq. Further analysis revealed that BUD31 inhibition results in extensive exon skipping and decreased abundance of long CDS isoforms. In particular, we identified BCL2L12, an anti-apoptotic BCL2 family member, as a functional splicing target of BUD31. BUD31 stimulates the inclusion of exon 3 to generate full-length BCL2L12 and promotes ovarian cancer progression. Knockdown of BUD31 or splice-switching antisense oligonucleotide treatment promotes exon 3 skipping and results in a truncated isoform of BCL2L12 that undergoes nonsense-mediated mRNA decay, and the cells subsequently undergo apoptosis. Our findings reveal BUD31-regulated exon inclusion as a critical factor in ovarian cancer cell survival and progression.