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

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

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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.

Original language	English (US)
Pages (from-to)	783-789
Number of pages	7
Journal	Nature Genetics
Volume	50
Issue number	6
DOIs	https://doi.org/10.1038/s41588-018-0118-8
State	Published - Jun 1 2018

ASJC Scopus subject areas

Genetics

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@article{03fcde3dd99642929b85875901cda616,

title = "3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk",

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.",

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

note = "Funding Information: This work was supported by US National Institutes of Health (NIH) grants R01HG007538, R01CA193466 and U54CA217297, Cancer Prevention Research Institute of Texas (CPRIT) grant RP150292 to W.L., CPRIT RP100107 to E.J.W. and A.-B.S., CPRIT RP140800 and Welch Foundation AU-1889 to E.J.W., and NIH RO1GM046454 and the Houston Endowment, Inc. to A.-B.S. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = jun,

day = "1",

doi = "10.1038/s41588-018-0118-8",

language = "English (US)",

volume = "50",

pages = "783--789",

journal = "Nature Genetics",

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T1 - 3′ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk

AU - Park, Hyun Jung

AU - Ji, Ping

AU - Kim, Soyeon

AU - Xia, Zheng

AU - Rodriguez, Benjamin

AU - Li, Lei

AU - Su, Jianzhong

AU - Chen, Kaifu

AU - Masamha, Chioniso P.

AU - Baillat, David

AU - Fontes-Garfias, Camila R.

AU - Shyu, Ann Bin

AU - Neilson, Joel R.

AU - Wagner, Eric J.

AU - Li, Wei

N1 - Funding Information: This work was supported by US National Institutes of Health (NIH) grants R01HG007538, R01CA193466 and U54CA217297, Cancer Prevention Research Institute of Texas (CPRIT) grant RP150292 to W.L., CPRIT RP100107 to E.J.W. and A.-B.S., CPRIT RP140800 and Welch Foundation AU-1889 to E.J.W., and NIH RO1GM046454 and the Houston Endowment, Inc. to A.-B.S. Publisher Copyright: © 2018 The Author(s).

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

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JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

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