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

• Published in: Nature communications Vol. 13; no. 1; pp. 6246 - 18
• Main Authors: Wang, Zixiang, Wang, Shourong, Qin, Junchao, Zhang, Xiyu, Lu, Gang, Liu, Hongbin, Guo, Haiyang, Wu, Ligang, Shender, Victoria O., Shao, Changshun, Kong, Beihua, Liu, Zhaojian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.10.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/105; 13/2; 13/31; 13/51; 13/89; 14/1; 14/19; 14/5; 14/63; 38/44; 38/90; 45/43; 45/71; 45/77; 45/91; 49/39; 631/208/1792; 631/45/500; 64/60; Alternative Splicing; Antisense oligonucleotides; Apoptosis; Cancer; Carcinoma, Ovarian Epithelial; Cell survival; Exon skipping; Female; Humanities and Social Sciences; Humans; Isoforms; Medical prognosis; mRNA turnover; multidisciplinary; Muscle Proteins - genetics; Nonsense-mediated mRNA decay; Nuclear Proteins - genetics; Oligonucleotides, Antisense; Ovarian cancer; Ovarian Neoplasms - genetics; Protein Isoforms - genetics; Proto-Oncogene Proteins c-bcl-2 - genetics; RNA Splicing - genetics; RNA Splicing Factors - genetics; Science; Science (multidisciplinary); Splicing; Splicing factors; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34042-w

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 demonstrate that spliceosome component BUD31 is increased in ovarian cancer, and its higher expression predicts worse prognosis. We characterize the BUD31-binding motif and find that BUD31 preferentially binds exon-intron regions near splicing sites. Further analysis reveals that BUD31 inhibition results in extensive exon skipping and a reduced production of long isoforms containing full coding sequence. In particular, we identify BCL2L12 , an anti-apoptotic BCL2 family member, as one of the functional splicing targets 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 for ovarian cancer cell survival and cancer progression. Altered expression of splicing factors can contribute to tumour progression. Here the authors show that splicing factor BUD31 enhances ovarian cancer progression by promoting exon inclusion in the anti-apoptotic BCL2 family member, BCL2L12.