Pan-cancer pervasive upregulation of 3′ UTR splicing drives tumourigenesis

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3′ UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3′ UTR splicing remains poorly understood as splic...

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Published in:	Nature cell biology Vol. 24; no. 6; pp. 928 - 939
Main Authors:	Chan, Jia Jia, Zhang, Bin, Chew, Xiao Hong, Salhi, Adil, Kwok, Zhi Hao, Lim, Chun You, Desi, Ng, Subramaniam, Nagavidya, Siemens, Angela, Kinanti, Tyas, Ong, Shane, Sanchez-Mejias, Avencia, Ly, Phuong Thao, An, Omer, Sundar, Raghav, Fan, Xiaonan, Wang, Shi, Siew, Bei En, Lee, Kuok Chung, Chong, Choon Seng, Lieske, Bettina, Cheong, Wai-Kit, Goh, Yufen, Fam, Wee Nih, Ooi, Melissa G., Koh, Bryan T. H., Iyer, Shridhar Ganpathi, Ling, Wen Huan, Chen, Jianbin, Yoong, Boon-Koon, Chanwat, Rawisak, Bonney, Glenn Kunnath, Goh, Brian K. P., Zhai, Weiwei, Fullwood, Melissa J., Wang, Wilson, Tan, Ker-Kan, Chng, Wee Joo, Dan, Yock Young, Pitt, Jason J., Roca, Xavier, Guccione, Ernesto, Vardy, Leah A., Chen, Leilei, Gao, Xin, Chow, Pierce K. H., Yang, Henry, Tay, Yvonne
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-06-2022 Nature Publishing Group
Subjects:	13/106 13/109 13/89 14/19 14/32 14/63 3' Untranslated regions 38/70 38/77 38/90 38/91 631/114/2114 631/208/1792 631/553/1833 631/67 64/60 82/1 82/29 96/106 Adenocarcinoma Antisense oligonucleotides Biomedical and Life Sciences Cancer Cancer Research Cell Biology Colon Developmental Biology Hepatocellular carcinoma Life Sciences Polyadenylation Post-transcription Splicing Stem Cells Tumorigenesis Tumors Up-regulation
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Summary:	Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3′ UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3′ UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3′ UTR splicing and present this in SpUR ( http://www.cbrc.kaust.edu.sa/spur/home/ ). 3′ UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3′ UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3′ UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3′ UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3′ UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics. Chan et al. report that 3′ UTR splicing is widespread and enhanced across different cancer types and is associated with more advanced tumour progression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1465-7392 1476-4679
DOI:	10.1038/s41556-022-00913-z