biostudies-literature00400Kim JHNCATS NIH HHSUAB | Comprehensive Cancer Center, University of Alabama at BirminghamNHLBI NIH HHSUAB | School of Medicine, University of Alabama at BirminghamNCI NIH HHSU.S. Department of Health & Human Services | National Institutes of Health5551https://www.ebi.ac.uk/biostudies/studies/S-EPMC8455679biostudies-literatureUnknown12(1)While dysregulation of RNA splicing has been recognized as an emerging target for cancer therapy, the functional significance of RNA splicing and individual splicing factors in brain tumors is poorly understood. Here, we identify SON as a master regulator that activates PTBP1-mediated oncogenic splicing while suppressing RBFOX2-mediated non-oncogenic neuronal splicing in glioblastoma multiforme (GBM). SON is overexpressed in GBM patients and SON knockdown causes failure in intron removal from the PTBP1 transcript, resulting in PTBP1 downregulation and inhibition of its downstream oncogenic splicing. Furthermore, SON forms a complex with hnRNP A2B1 and antagonizes RBFOX2, which leads to skipping of RBFOX2-targeted cassette exons, including the PTBP2 neuronal exon. SON knockdown inhibits proliferation and clonogenicity of GBM cells in vitro and significantly suppresses tumor growth in orthotopic xenografts in vivo. Collectively, our study reveals that SON-mediated RNA splicing is a GBM vulnerability, implicating SON as a potential therapeutic target in brain tumors.Nature communicationsSON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity.PMC8455679R01CA148629R01HL136432R01CA190688UL1TR003096-01R01CA236911R01 HL136432R01 CA190688UL1 TR003096R01 CA236911R01 CA148629Li JStone JKRichard AJeong KAhn EEGillespie GYMurphy JMKim JHVukadin LLim SSFlemington EKTran JSobol RW40falseSON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity.While dysregulation of RNA splicing has been recognized as an emerging target for cancer therapy, the functional significance of RNA splicing and individual splicing factors in brain tumors is poorly understood. Here, we identify SON as a master regulator that activates PTBP1-mediated oncogenic splicing while suppressing RBFOX2-mediated non-oncogenic neuronal splicing in glioblastoma multiforme (GBM). SON is overexpressed in GBM patients and SON knockdown causes failure in intron removal from the PTBP1 transcript, resulting in PTBP1 downregulation and inhibition of its downstream oncogenic splicing. Furthermore, SON forms a complex with hnRNP A2B1 and antagonizes RBFOX2, which leads to skipping of RBFOX2-targeted cassette exons, including the PTBP2 neuronal exon. SON knockdown inhibits proliferation and clonogenicity of GBM cells in vitro and significantly suppresses tumor growth in orthotopic xenografts in vivo. Collectively, our study reveals that SON-mediated RNA splicing is a GBM vulnerability, implicating SON as a potential therapeutic target in brain tumors.2021-01-01T00:00:00Z2021 Sep2024-11-12T08:23:02.601Z2022-02-11T11:52:05.134ZS-EPMC84556793454848910.1038/s41467-021-25892-x