Open AccessTargeting the Notch-regulated non-coding RNA TUG1 for glioma treatment
Author(s) -
Keisuke Katsushima,
Atsushi Natsume,
Fumiharu Ohka,
Keiko Shinjo,
Akira Hatanaka,
Norihisa Ichimura,
Shinya Sato,
Satoru Takahashi,
Hiroshi Kimurâ,
Yasushi Totoki,
Tatsuhiro Shibata,
Mitsuru Naito,
Hyun Jin Kim,
Kanjiro Miyata,
Kazunori Kataoka,
Yutaka Kondo
Publication year - 2016
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms13616
Subject(s) - notch signaling pathway , biology , glioma , cancer research , histone , stem cell , rna interference , microbiology and biotechnology , rna , gene , genetics , signal transduction
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.