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Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.

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 ( 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.

SUBMITTER: Chan JJ

PROVIDER: S-EPMC9203280 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.

Chan Jia Jia JJ Zhang Bin B Chew Xiao Hong XH Salhi Adil A Kwok Zhi Hao ZH Lim Chun You CY Desi Ng N Subramaniam Nagavidya N Siemens Angela A Kinanti Tyas T Ong Shane S Sanchez-Mejias Avencia A Ly Phuong Thao PT An Omer O Sundar Raghav R Fan Xiaonan X Wang Shi S Siew Bei En BE Lee Kuok Chung KC Chong Choon Seng CS Lieske Bettina B Cheong Wai-Kit WK Goh Yufen Y Fam Wee Nih WN Ooi Melissa G MG Koh Bryan T H BTH Iyer Shridhar Ganpathi SG Ling Wen Huan WH Chen Jianbin J Yoong Boon-Koon BK Chanwat Rawisak R Bonney Glenn Kunnath GK Goh Brian K P BKP Zhai Weiwei W Fullwood Melissa J MJ Wang Wilson W Tan Ker-Kan KK Chng Wee Joo WJ Dan Yock Young YY Pitt Jason J JJ Roca Xavier X Guccione Ernesto E Vardy Leah A LA Chen Leilei L Gao Xin X Chow Pierce K H PKH Yang Henry H Tay Yvonne Y

Nature cell biology 20220526 6

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/spu ...[more]

PMID: 35618746

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Project description:BackgroundRole of TC2N in carcinogenesis has been largely unfathomed until recently when it was identified as a novel oncogene in lung cancer. Subsequently, a tumour suppressor role of TC2N was reported in breast cancer. It is therefore highly relevant to investigate TC2N molecular partners/mechanisms on a larger scale including a wider range of tumour types.MethodsWe investigated TC2N mRNA expression, its promoter methylation levels, effects of TC2N transcription on overall patient survival, somatic mutations in TC2N gene and correlation between TC2N mRNA expression and other cancer genes in pan-cancer by using data available from the Cancer Genome Atlas (TCGA) and the Genotype Tissue Expression (GTEx) databases.ResultsTC2N mRNA expression was differentially regulated in 9/33 TCGA tumour types. Of these 9 tumours, 5 tumour types (cholangiocarcinoma, ovarian-serous-cystadenocarcinoma, rectal-adenocarcinoma, stomach-adenocarcinoma and thymoma) had significantly higher TC2N mRNA expression while 4 (pheochromocytoma-and-paraganglioma, skin-cutaneous-melanoma, thyroid-carcinoma and uterine-carcinosarcoma) had significantly lower TC2N mRNA expression compared to matched and normal controls. TC2N promoter was hypermethylated in most cancers while hypomethylated in head-and-neck-squamous-cell-carcinoma and kidney-renal-clear-cell carcinoma. TC2N transcription was positively correlated with transcription of several other cancer genes including genes from Myc, cell-cycle, Nrf2, Wnt, PI3K, Hippo, Notch, TGFβ and RAS/RTK pathways. Poor prognosis was associated with higher TC2N mRNA levels in pancreatic-adenocarcinoma and brain-lower-grade-glioma and lower TC2N mRNA levels in kidney-renal-clear-cell-carcinoma, mesothelioma, sarcoma and skin-cutaneous melanoma. Functional protein partners of TC2N were identified as STX2, SMEK1, SMEK2, STXBP5, SCARA5, MMRN1, CATSPER2, CATSPERB, CLEC4M and STAB2. Many of these proteins are key players in carcinogenesis of various cancers. Highest pathogenic somatic mutation rates in TC2N were found in skin-cutaneous-melanoma, uterine-corpus-endometrial-carcinoma, colon-endocervical-adenocarcinoma, bladder-urothelial-carcinoma and breast-invasive-carcinoma.ConclusionOur findings unravel several un-explored avenues related to the role of TC2N in tumourigenesis of several cancers, suggesting TC2N as an important player and a potential candidate for tumour-therapy.

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Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.

Publications

Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.

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