title: Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment.
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.
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Katsushima
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Natsume
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.|Department of Neurosurgery, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Ohka
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Shinjo
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hatanaka
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ichimura
authors.affiliation: Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Sato
authors.affiliation: Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology, Tokyo 226-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Cancer Genomics, National Cancer Center, Tokyo 104-0045, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
authors.affiliation: Division of Cancer Genomics, National Cancer Center, Tokyo 104-0045, Japan.|Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Naito
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656 Japan.
authors.forename: Kanjiro
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656 Japan.|Innovation Center of Nanomedicine, Kawasaki Institute of Industry Promotion, Kawasaki 210-0821, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo 102-8666, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000628:therapy*; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D051881:Receptor, Notch1; D055748:SOXB1 Transcription Factors; C000598536:TUG1 long noncoding RNA, human; D050986:YY1 Transcription Factor; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2