SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity.
Animals
Brain Neoplasms
/ genetics
Cell Cycle
/ genetics
Cell Line, Tumor
Cell Proliferation
DNA-Binding Proteins
/ antagonists & inhibitors
Exons
Gene Expression Regulation, Neoplastic
Glioblastoma
/ genetics
Heterogeneous-Nuclear Ribonucleoprotein Group A-B
/ genetics
Heterogeneous-Nuclear Ribonucleoproteins
/ genetics
Heterografts
Humans
Introns
Mice
Minor Histocompatibility Antigens
/ genetics
Nerve Tissue Proteins
/ genetics
Neuroglia
/ metabolism
Neurons
/ metabolism
Polypyrimidine Tract-Binding Protein
/ genetics
RNA Splicing
RNA Splicing Factors
/ genetics
RNA, Messenger
/ genetics
RNA, Small Interfering
/ genetics
Repressor Proteins
/ genetics
Signal Transduction
Spheroids, Cellular
/ metabolism
Survival Analysis
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 09 2021
21 09 2021
Historique:
received:
15
04
2019
accepted:
01
09
2021
entrez:
22
9
2021
pubmed:
23
9
2021
medline:
15
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34548489
doi: 10.1038/s41467-021-25892-x
pii: 10.1038/s41467-021-25892-x
pmc: PMC8455679
doi:
Substances chimiques
DNA-Binding Proteins
0
Heterogeneous-Nuclear Ribonucleoprotein Group A-B
0
Heterogeneous-Nuclear Ribonucleoproteins
0
Minor Histocompatibility Antigens
0
Nerve Tissue Proteins
0
PTBP1 protein, human
0
PTBP2 protein, human
0
RBFOX2 protein, human
0
RNA Splicing Factors
0
RNA, Messenger
0
RNA, Small Interfering
0
Repressor Proteins
0
SON protein, human
0
Polypyrimidine Tract-Binding Protein
139076-35-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
5551Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR003096
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA236911
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA148629
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190688
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL136432
Pays : United States
Informations de copyright
© 2021. The Author(s).
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