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

Hyun Jung Park; Ping Ji; Soyeon Kim; Zheng Xia; Benjamin Rodriguez; Lei Li; Jianzhong Su; Kaifu Chen; Chioniso P Masamha; David Baillat; Camila R Fontes-Garfias; Ann-Bin Shyu; Joel R Neilson; Eric J Wagner; Wei Li

doi:10.1038/s41588-018-0118-8

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

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

Authors

Hyun Jung Park^{1

2

3}, Ping Ji⁴, Soyeon Kim⁵, Zheng Xia^{1

2}, Benjamin Rodriguez^{1

2}, Lei Li^{1

2}, Jianzhong Su^{1

2}, Kaifu Chen^{1

2}, Chioniso P Masamha⁶, David Baillat⁴, Camila R Fontes-Garfias⁴, Ann-Bin Shyu⁷, Joel R Neilson⁸, Eric J Wagner⁹, Wei Li^{10

11}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions*
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Genes, Tumor Suppressor*
HeLa Cells
Humans
MCF-7 Cells
MicroRNAs / genetics
Neoplasms / genetics*
Proto-Oncogene Mas
Proto-Oncogenes / genetics
RNA / genetics*
RNA, Messenger / genetics

Substances

3' Untranslated Regions
MAS1 protein, human
MicroRNAs
Proto-Oncogene Mas
RNA, Messenger
RNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding