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Title: Pan-cancer pervasive upregulation of 3 ' UTR splicing drives tumourigenesis
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 TH
Iyer, Shridhar Ganpathi 
Ling, Wen Huan 
Chen, Jianbin 
Yoong, Boon-Koon
Chanwat, Rawisak
Bonney, Glenn Kunnath
Goh, Brian KP 
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 KH 
Yang, Henry
Tay, Yvonne 
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Issue Date: 26-May-2022
Citation: 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 TH, Iyer, Shridhar Ganpathi, Ling, Wen Huan, Chen, Jianbin, Yoong, Boon-Koon, Chanwat, Rawisak, Bonney, Glenn Kunnath, Goh, Brian KP, 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 KH, Yang, Henry, Tay, Yvonne (2022-05-26). Pan-cancer pervasive upregulation of 3 ' UTR splicing drives tumourigenesis. NATURE CELL BIOLOGY 24 (6) : 928-+. ScholarBank@NUS Repository.
Abstract: 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 ( ). 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.
ISSN: 14657392
DOI: 10.1038/s41556-022-00913-z
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