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Published on: October 4, 2019
Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment
Keisuke Katsushima1, Atsushi Natsume2, Fumiharu Ohka1,2
1Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
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.
Insights
Targeting TUG1, a Notch-induced lncRNA, inhibits glioma stem cell self-renewal and growth. This approach offers a specific therapeutic strategy for eliminating glioma stem cells by promoting differentiation.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Targeting cancer stem cell self-renewal is crucial for effective cancer therapy.
- The Notch signaling pathway plays a key role in maintaining the stemness of glioma stem cells (GSCs).
- Understanding cancer-specific Notch regulation is essential for developing targeted therapies.
Purpose of the Study:
- To investigate the role of the Notch-lncRNA axis in regulating GSC self-renewal.
- To identify specific molecular targets for glioma therapy.
- To evaluate the therapeutic potential of targeting TUG1 in GSCs.
Main Methods:
- Investigated Notch1 activation and its downstream effects in GSCs.
- Analyzed the function of the long non-coding RNA TUG1 in GSC self-renewal and differentiation.
- Examined the molecular mechanisms of TUG1, including its interaction with miR-145 and polycomb repressive complex 2.
- Evaluated the in vivo efficacy of antisense oligonucleotides targeting TUG1 in a GSC model.
Main Results:
- Notch1 activation in GSCs specifically induces the expression of the lncRNA TUG1.
- TUG1 promotes GSC self-renewal by sponging miR-145 in the cytoplasm.
- TUG1 recruits polycomb to repress differentiation genes via histone H3K27 methylation in the nucleus.
- Intravenous administration of TUG1-targeting antisense oligonucleotides induced GSC differentiation and repressed GSC growth in vivo.
Conclusions:
- The Notch-lncRNA axis is critical for regulating glioma cell self-renewal.
- TUG1 is a key mediator of GSC stemness.
- Targeting TUG1 represents a specific and potent therapeutic strategy for eliminating the GSC population in glioma.
