Splicing factor hnRNPH drives an oncogenic splicing switch in gliomas Journal Article
| Authors: | Lefave, C. V.; Squatrito, M.; Vorlova, S.; Rocco, G. L.; Brennan, C. W.; Holland, E. C.; Pan, Y. X.; Cartegni, L. |
| Article Title: | Splicing factor hnRNPH drives an oncogenic splicing switch in gliomas |
| Abstract: | In tumours, aberrant splicing generates variants that contribute to multiple aspects of tumour establishment, progression and maintenance. We show that in glioblastoma multiforme (GBM) specimens, death-domain adaptor protein Insuloma-Glucagonoma protein 20 (IG20) is consistently aberrantly spliced to generate an antagonist, anti-apoptotic isoform (MAP-kinase activating death domain protein, MADD), which effectively redirects TNF-Î ±/TRAIL-induced death signalling to promote survival and proliferation instead of triggering apoptosis. Splicing factor hnRNPH, which is upregulated in gliomas, controls this splicing event and similarly mediates switching to a ligand-independent, constitutively active Recepteur dĝ€2Origine Nantais (RON) tyrosine kinase receptor variant that promotes migration and invasion. The increased cell death and the reduced invasiveness caused by hnRNPH ablation can be rescued by the targeted downregulation of IG20/MADD exon 16-or RON exon 11-containing variants, respectively, using isoform-specific knockdown or splicing redirection approaches. Thus, hnRNPH activity appears to be involved in the pathogenesis and progression of malignant gliomas as the centre of a splicing oncogenic switch, which might reflect reactivation of stem cell patterns and mediates multiple key aspects of aggressive tumour behaviour, including evasion from apoptosis and invasiveness. © 2011 European Molecular Biology Organization | All Rights Reserved. |
| Journal Title: | EMBO Journal |
| Volume: | 30 |
| Issue: | 19 |
| ISSN: | 0261-4189 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2011-09-13 |
| Start Page: | 4084 |
| End Page: | 4097 |
| Language: | English |
| DOI: | 10.1038/emboj.2011.259 |
| PROVIDER: | scopus |
| PUBMED: | 21915099 |
| PMCID: | PMC3209773 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2011" - "CODEN: EMJOD" - "Source: Scopus" |
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