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

Zixiang Wang, Shourong Wang, Junchao Qin, Xiyu Zhang, Gang Lu, Hongbin Liu, Haiyang Guo, View ORCID ProfileLigang Wu, Changshun Shao, Beihua Kong, View ORCID ProfileZhaojian Liu
doi: https://doi.org/10.1101/2022.01.19.476862
Zixiang Wang
1Key Laboratory of Experimental Teratology, Ministry of Education, Department of Cell Biology, School of Basic Medical Science, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
2Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China
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Shourong Wang
1Key Laboratory of Experimental Teratology, Ministry of Education, Department of Cell Biology, School of Basic Medical Science, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Junchao Qin
1Key Laboratory of Experimental Teratology, Ministry of Education, Department of Cell Biology, School of Basic Medical Science, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
2Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China
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Xiyu Zhang
1Key Laboratory of Experimental Teratology, Ministry of Education, Department of Cell Biology, School of Basic Medical Science, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Gang Lu
3CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
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Hongbin Liu
4Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
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Haiyang Guo
5Department of Clinical Laboratory, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
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Ligang Wu
6Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
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Changshun Shao
7Institutes for Translational Medicine, Soochow University, Suzhou, China.
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  • For correspondence: liujian9782@sdu.edu.cn kongbeihua@sdu.edu.cn shaoc@suda.edu.cn
Beihua Kong
1Key Laboratory of Experimental Teratology, Ministry of Education, Department of Cell Biology, School of Basic Medical Science, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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  • For correspondence: liujian9782@sdu.edu.cn kongbeihua@sdu.edu.cn shaoc@suda.edu.cn
Zhaojian Liu
1Key Laboratory of Experimental Teratology, Ministry of Education, Department of Cell Biology, School of Basic Medical Science, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
2Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China
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  • ORCID record for Zhaojian Liu
  • For correspondence: liujian9782@sdu.edu.cn kongbeihua@sdu.edu.cn shaoc@suda.edu.cn
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SUMMARY

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.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 21, 2022.
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Splicing factor BUD31 promotes ovarian cancer progression through sustaining the expression of anti-apoptotic BCL2L12
Zixiang Wang, Shourong Wang, Junchao Qin, Xiyu Zhang, Gang Lu, Hongbin Liu, Haiyang Guo, Ligang Wu, Changshun Shao, Beihua Kong, Zhaojian Liu
bioRxiv 2022.01.19.476862; doi: https://doi.org/10.1101/2022.01.19.476862
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Splicing factor BUD31 promotes ovarian cancer progression through sustaining the expression of anti-apoptotic BCL2L12
Zixiang Wang, Shourong Wang, Junchao Qin, Xiyu Zhang, Gang Lu, Hongbin Liu, Haiyang Guo, Ligang Wu, Changshun Shao, Beihua Kong, Zhaojian Liu
bioRxiv 2022.01.19.476862; doi: https://doi.org/10.1101/2022.01.19.476862

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