Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo

Hirashima, Kyotaro; Seimiya, Hiroyuki

doi:10.1093/nar/gkv063

Cited by 66 publications

(63 citation statements)

References 31 publications

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“…There have been fewer studies on the immunological effects of telomeric RNAs. However, a recent report showed that telomere RNA forming G-quadruplex structures can induce global changes in gene expression, including suppression of innate immune sensing genes (63).…”

Section: Discussionmentioning

confidence: 99%

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

Wang

Deng

Dahmane

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Telomeric repeat-containing RNA (TERRA) has been identified as a telomere-associated regulator of chromosome end protection. Here, we report that TERRA can also be found in extracellular fractions that stimulate innate immune signaling. We identified extracellular forms of TERRA in mouse tumor and embryonic brain tissue, as well as in human tissue culture cell lines using RNA in situ hybridization. RNA-seq analyses revealed TERRA to be among the most highly represented transcripts in extracellular fractions derived from both normal and cancer patient blood plasma. Cell-free TERRA (cfTERRA) could be isolated from the exosome fractions derived from human lymphoblastoid cell line (LCL) culture media. cfTERRA is a shorter form (∼200 nt) of cellular TERRA and copurifies with CD63-and CD83-positive exosome vesicles that could be visualized by cyro-electron microscopy. These fractions were also enriched for histone proteins that physically associate with TERRA in extracellular ChIP assays. Incubation of cfTERRAcontaining exosomes with peripheral blood mononuclear cells stimulated transcription of several inflammatory cytokine genes, including TNFα, IL6, and C-X-C chemokine 10 (CXCL10) Exosomes engineered with elevated TERRA or liposomes with synthetic TERRA further stimulated inflammatory cytokines, suggesting that exosome-associated TERRA augments innate immune signaling. These findings imply a previously unidentified extrinsic function for TERRA and a mechanism of communication between telomeres and innate immune signals in tissue and tumor microenvironments.TERRA | telomere | exosome | innate immunity | cytokine

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Section: Discussionmentioning

confidence: 99%

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

Wang

Deng

Dahmane

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Samples were then incubated with a horseradish peroxidase (HRP)-conjugated anti-FLAG antibody (Abcam, Cambridge, UK) and the HRP substrate TMB (Roche, Mannheim, Germany), followed by measurement of absorbance at 450 nm. Circular dichroism spectra for confirmation of G-quadruplex formation were produced as described [23]. Sequences of oligonucleotides (oligos) used are as follows: KIT2 (G4 motif) 5′-CGGGCGGGCGCGAGGGAGGGG-3′; hTELO (G4 motif) 5′-GG(TTAGGG) x4 TTAG-3′; and control DNA (non-G4) 5′-GGCATAGTGCGTGGGCG-3′.…”

Section: Methodsmentioning

confidence: 99%

G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells

Hasegawa

Okabe

Okamoto

et al. 2016

Biochemical and Biophysical Research Communications

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Glioblastoma (GBM) is an invariably fatal brain tumor in which a small subpopulation of self-renewable glioma stem cells (GSCs) contributes to tumor propagation and relapse. Targeting GSCs could therefore have a significant clinical impact for GBM. Telomestatin is a naturally-occurring compound that preferentially impairs GSC growth by perturbing transcription and inducing a DNA damage response. Telomestatin stabilizes G-quadruplexes (G4s), which are guanine-rich four-strand nucleic acid structures observed in vitro and in vivo. However, the mechanism underlying the GSC-selective nature of the DNA damage response remains unknown. Here we demonstrate that GSCs are more susceptible to telomestatin-induced telomere dysfunction and replication stress when compared with GSC-derived non-stem glioma cells (NSGCs). Telomestatin induced dissociation of the telomere-capping protein TRF2 from telomeres, leading to telomeric DNA damage in GSCs–but not in NSGCs. BIBR1532, a telomerase catalytic inhibitor, did not preferentially inhibit GSC growth, suggesting that telomestatin promotes telomere dysfunction in a telomerase-independent manner. GSCs and NSGCs had comparable levels of G4s in their nuclei, and both responded to telomestatin with phosphorylation of RPA2 at Ser33–a hallmark of replication stress. However, activation of the checkpoint kinase Chk1, induction of a DNA damage response, and subsequent growth inhibition occurred only in telomestatin-treated GSCs. These observations suggest that telomestatin impairs GSC growth through removal of TRF2 from telomeres and potent activation of the replication stress response pathway. Therefore, a novel G4-directed therapeutic strategy could specifically target cancer stem cells in GBM.

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“…RNA was extracted, and GeneChip microarray analysis was performed as described [13]. The microarray data were deposited in the Gene Expression Omnibus database (www.ncbi.nlm.nih.gov/geo) under accession number GSE74304.…”

Section: Methodsmentioning

confidence: 99%

Senescence from glioma stem cell differentiation promotes tumor growth

Ouchi

Okabe

Migita

et al. 2016

Biochemical and Biophysical Research Communications

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Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs’ role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins.

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Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo

Cited by 66 publications

References 31 publications

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells

Senescence from glioma stem cell differentiation promotes tumor growth

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