RRC ID 50503
Author Katsushima K, Natsume A, Ohka F, Shinjo K, Hatanaka A, Ichimura N, Sato S, Takahashi S, Kimura H, Totoki Y, Shibata T, Naito M, Kim HJ, Miyata K, Kataoka K, Kondo Y.
Title Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment.
Journal Nat Commun
Abstract Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1. TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with antisense oligonucleotides targeting TUG1 coupled with a drug delivery system induces GSC differentiation and efficiently represses GSC growth in vivo. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population.
Volume 7
Pages 13616
Published 2016-12-6
DOI 10.1038/ncomms13616
PII ncomms13616
PMID 27922002
PMC PMC5150648
MeSH Animals Brain Neoplasms / genetics* Brain Neoplasms / therapy* Carcinogenesis / genetics Carcinogenesis / pathology Cell Differentiation / genetics Enhancer of Zeste Homolog 2 Protein / metabolism Exons / genetics Female Gene Expression Regulation, Neoplastic Glioma / genetics* Glioma / therapy* Humans Mice, Inbred NOD Mice, SCID MicroRNAs / genetics MicroRNAs / metabolism Neoplastic Stem Cells / metabolism Neoplastic Stem Cells / pathology Neurons / metabolism Polycomb Repressive Complex 2 / metabolism Protein Binding Proto-Oncogene Proteins c-myc / metabolism RNA, Long Noncoding / genetics RNA, Long Noncoding / metabolism* RNA, Messenger / genetics RNA, Messenger / metabolism Receptor, Notch1 / metabolism* SOXB1 Transcription Factors / metabolism Xenograft Model Antitumor Assays YY1 Transcription Factor / metabolism
IF 12.353
Resource
DNA material pTnT-TUG1 exon1 (RDB15794) pTnT-TUG1 exon2 (RDB15795) pTnT-TUG1 exon3 (RDB15796).