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Nat Genet. 2018 Jun;50(6):783-789. doi: 10.1038/s41588-018-0118-8. Epub 2018 May 21.

3' UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk.

Author information

1
Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
2
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
3
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
4
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
5
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
6
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN, USA.
7
Department of Biochemistry and Molecular Biology, University of Texas, McGovern Medical School, Houston, TX, USA.
8
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
9
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA. ejwagner@utmb.edu.
10
Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. WL1@bcm.edu.
11
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. WL1@bcm.edu.

Abstract

Widespread mRNA 3' UTR shortening through alternative polyadenylation 1 promotes tumor growth in vivo 2 . A prevailing hypothesis is that it induces proto-oncogene expression in cis through escaping microRNA-mediated repression. Here we report a surprising enrichment of 3'UTR shortening among transcripts that are predicted to act as competing-endogenous RNAs (ceRNAs) for tumor-suppressor genes. Our model-based analysis of the trans effect of 3' UTR shortening (MAT3UTR) reveals a significant role in altering ceRNA expression. MAT3UTR predicts many trans-targets of 3' UTR shortening, including PTEN, a crucial tumor-suppressor gene 3 involved in ceRNA crosstalk 4 with nine 3'UTR-shortening genes, including EPS15 and NFIA. Knockdown of NUDT21, a master 3' UTR-shortening regulator 2 , represses tumor-suppressor genes such as PHF6 and LARP1 in trans in a miRNA-dependent manner. Together, the results of our analysis suggest a major role of 3' UTR shortening in repressing tumor-suppressor genes in trans by disrupting ceRNA crosstalk, rather than inducing proto-oncogenes in cis.

Comment in

PMID:
29785014
PMCID:
PMC6689271
DOI:
10.1038/s41588-018-0118-8
[Indexed for MEDLINE]
Free PMC Article

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