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-α/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 d'Origine 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.
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Clare V
authors.initials: CV
authors.lastname: Lefave
authors.forename: Massimo
authors.initials: M
authors.lastname: Squatrito
authors.forename: Sandra
authors.initials: S
authors.lastname: Vorlova
authors.forename: Gina L
authors.initials: GL
authors.lastname: Rocco
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Brennan
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.forename: Ying-Xian
authors.initials: YX
authors.lastname: Pan
authors.forename: Luca
authors.initials: L
authors.lastname: Cartegni
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006367:HeLa Cells; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D012326:RNA Splicing; D050436:Regulatory Elements, Transcriptional
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; C105852:MADD protein, human