Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment

Keisuke Katsushima, Atsushi Natsume, Fumiharu Ohka, Keiko Shinjo, Akira Hatanaka, Norihisa Ichimura, Shinya Sato, Satoru Takahashi, Hiroshi Kimura, Yasushi Totoki, Tatsuhiro Shibata, Mitsuru Naito, Hyun Jin Kim, Kanjiro Miyata, Kazunori Kataoka and Yutaka Kondo ()
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Keisuke Katsushima: Nagoya City University Graduate School of Medical Sciences
Atsushi Natsume: Nagoya University School of Medicine
Fumiharu Ohka: Nagoya City University Graduate School of Medical Sciences
Keiko Shinjo: Nagoya City University Graduate School of Medical Sciences
Akira Hatanaka: Nagoya City University Graduate School of Medical Sciences
Norihisa Ichimura: Nagoya City University Graduate School of Medical Sciences
Shinya Sato: Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences
Satoru Takahashi: Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences
Hiroshi Kimura: Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology
Yasushi Totoki: National Cancer Center
Tatsuhiro Shibata: National Cancer Center
Mitsuru Naito: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo
Hyun Jin Kim: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo
Kanjiro Miyata: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo
Kazunori Kataoka: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo
Yutaka Kondo: Nagoya City University Graduate School of Medical Sciences

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13616

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