The RNA Binding Protein IMP2 Preserves Glioblastoma Stem Cells by Preventing let-7 Target Gene Silencing
Nils Degrauwe,
Tommy B. Schlumpf,
Michalina Janiszewska,
Patricia Martin,
Alexandra Cauderay,
Paolo Provero,
Nicolo Riggi,
Mario-L. Suvà,
Renato Paro,
Ivan Stamenkovic
Affiliations
Nils Degrauwe
Division of Experimental Pathology, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
Tommy B. Schlumpf
Department of Biosystems Science and Engineering, ETH Zürich, Mattenstrasse 26, 4058 Basel, Switzerland
Michalina Janiszewska
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
Patricia Martin
Division of Experimental Pathology, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
Alexandra Cauderay
Division of Experimental Pathology, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
Paolo Provero
Department of Molecular Biotechnology and Life Sciences, University of Turin, Turin 10126, Italy
Nicolo Riggi
Division of Experimental Pathology, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
Mario-L. Suvà
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Renato Paro
Department of Biosystems Science and Engineering, ETH Zürich, Mattenstrasse 26, 4058 Basel, Switzerland
Ivan Stamenkovic
Division of Experimental Pathology, Institute of Pathology, CHUV, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland
Cancer stem cells (CSCs) can drive tumor growth, and their maintenance may rely on post-transcriptional regulation of gene expression, including that mediated by microRNAs (miRNAs). The let-7 miRNA family has been shown to induce differentiation by silencing stem cell programs. Let-7-mediated target gene suppression is prevented by LIN28A/B, which reduce let-7 biogenesis in normal embryonic and some cancer stem cells and ensure maintenance of stemness. Here, we find that glioblastoma stem cells (GSCs) lack LIN28 and express both let-7 and their target genes, suggesting LIN28-independent protection from let-7 silencing. Using photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP), we show that insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) binds to let-7 miRNA recognition elements (MREs) and prevents let-7 target gene silencing. Our observations define the RNA-binding repertoire of IMP2 and identify a mechanism whereby it supports GSC and neural stem cell specification.
