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

Courtney K. JnBaptiste; Allan M. Gurtan; Kevin K. Thai; Victoria Lu; Arjun Bhutkar; Mei-Ju Su; Asaf Rotem; Tyler Jacks; Phillip A. Sharp

doi:10.1101/gad.296301.117

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

¹Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
²David H. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
³Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA;
⁴Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA

Corresponding author: sharppa{at}mit.edu

Abstract

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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Footnotes

Supplemental material is available for this article.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.296301.117.

Received January 16, 2017.
Accepted March 20, 2017.

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