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Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1–3 family

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression critical for organismal viability. Changes in miRNA activity are common in cancer, but how these changes relate to subsequent alterations in transcription and the process of tumorigenesis is not well understood. Here, we repor...

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Autores principales: JnBaptiste, Courtney K., Gurtan, Allan M., Thai, Kevin K., Lu, Victoria, Bhutkar, Arjun, Su, Mei-Ju, Rotem, Asaf, Jacks, Tyler, Sharp, Phillip A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411708/
https://www.ncbi.nlm.nih.gov/pubmed/28446596
http://dx.doi.org/10.1101/gad.296301.117
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author JnBaptiste, Courtney K.
Gurtan, Allan M.
Thai, Kevin K.
Lu, Victoria
Bhutkar, Arjun
Su, Mei-Ju
Rotem, Asaf
Jacks, Tyler
Sharp, Phillip A.
author_facet JnBaptiste, Courtney K.
Gurtan, Allan M.
Thai, Kevin K.
Lu, Victoria
Bhutkar, Arjun
Su, Mei-Ju
Rotem, Asaf
Jacks, Tyler
Sharp, Phillip A.
author_sort JnBaptiste, Courtney K.
collection PubMed
description MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression critical for organismal viability. Changes in miRNA activity are common in cancer, but how these changes relate to subsequent alterations in transcription and the process of tumorigenesis is not well understood. Here, we report a deep transcriptional, oncogenic network regulated by miRNAs. We present analysis of the gene expression and phenotypic changes associated with global miRNA restoration in miRNA-deficient fibroblasts. This analysis uncovers a miRNA-repressed network containing oncofetal genes Imp1, Imp2, and Imp3 (Imp1–3) that is up-regulated primarily transcriptionally >100-fold upon Dicer loss and is resistant to resilencing by complete restoration of miRNA activity. This Dicer-resistant epigenetic switch confers tumorigenicity to these cells. Let-7 targets Imp1–3 are required for this tumorigenicity and feed back to reinforce and sustain expression of the oncogenic network. Together, these Dicer-resistant genes constitute an mRNA expression signature that is present in numerous human cancers and is associated with poor survival.
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spelling pubmed-54117082017-10-01 Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1–3 family JnBaptiste, Courtney K. Gurtan, Allan M. Thai, Kevin K. Lu, Victoria Bhutkar, Arjun Su, Mei-Ju Rotem, Asaf Jacks, Tyler Sharp, Phillip A. Genes Dev Research Paper MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression critical for organismal viability. Changes in miRNA activity are common in cancer, but how these changes relate to subsequent alterations in transcription and the process of tumorigenesis is not well understood. Here, we report a deep transcriptional, oncogenic network regulated by miRNAs. We present analysis of the gene expression and phenotypic changes associated with global miRNA restoration in miRNA-deficient fibroblasts. This analysis uncovers a miRNA-repressed network containing oncofetal genes Imp1, Imp2, and Imp3 (Imp1–3) that is up-regulated primarily transcriptionally >100-fold upon Dicer loss and is resistant to resilencing by complete restoration of miRNA activity. This Dicer-resistant epigenetic switch confers tumorigenicity to these cells. Let-7 targets Imp1–3 are required for this tumorigenicity and feed back to reinforce and sustain expression of the oncogenic network. Together, these Dicer-resistant genes constitute an mRNA expression signature that is present in numerous human cancers and is associated with poor survival. Cold Spring Harbor Laboratory Press 2017-04-01 /pmc/articles/PMC5411708/ /pubmed/28446596 http://dx.doi.org/10.1101/gad.296301.117 Text en © 2017 JnBaptiste et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
JnBaptiste, Courtney K.
Gurtan, Allan M.
Thai, Kevin K.
Lu, Victoria
Bhutkar, Arjun
Su, Mei-Ju
Rotem, Asaf
Jacks, Tyler
Sharp, Phillip A.
Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1–3 family
title Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1–3 family
title_full Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1–3 family
title_fullStr Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1–3 family
title_full_unstemmed Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1–3 family
title_short Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1–3 family
title_sort dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal imp1–3 family
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411708/
https://www.ncbi.nlm.nih.gov/pubmed/28446596
http://dx.doi.org/10.1101/gad.296301.117
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