Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells

Bai, Yun; Lathia, Justin D.; Zhang, Peisu; Flavahan, William; Rich, Jeremy; Mattson, Mark P.

doi:10.1002/glia.22708

Cited by 37 publications

(30 citation statements)

References 64 publications

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“…66 GSCs were enriched using established stem cells marker CD133 from primary GBMs and U251-GBM cells by labeling with PE-conjugated CD133 antibody and sorting by flow cytometry. Although other putative stem cell markers were used previously to enrich GSCs including SSEA-1, 67 CD44 68 and integrin α 6 69 and L1CAM, 70 CD133 has been shown to be a widely used marker of self-renewing and tumorigenic GBM cells, 6,71–73 therefore, we have used this marker in our studies. To induce the differentiation, CD133-postive GSCs were cultured in 10% FBS for 7 days.…”

Section: Methodsmentioning

confidence: 99%

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

et al. 2016

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Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models. Our results suggested that KDM1A is highly expressed in GSCs and knockdown of KDM1A using shRNA-reduced GSCs stemness and induced the differentiation. Pharmacological inhibition of KDM1A using NCL-1 and NCD-38 significantly reduced the cell viability, neurosphere formation and induced apoptosis of GSCs with little effect on differentiated cells. In preclinical studies using orthotopic models, NCL-1 and NCD-38 significantly reduced GSCs-driven tumor progression and improved mice survival. RNA-sequencing analysis showed that KDM1A inhibitors modulate several pathways related to stemness, differentiation and apoptosis. Mechanistic studies showed that KDM1A inhibitors induce activation of the unfolded protein response (UPR) pathway. These results strongly suggest that selective targeting of KDM1A using NCL-1 and NCD-38 is a promising therapeutic strategy for elimination of GSCs.

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Section: Methodsmentioning

confidence: 99%

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

et al. 2016

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“…46 An isoform of REST, hREST4, counters the genesilencing effect of REST in a dominant negative fashion. Depending on the cell context, TRF2 could either stabilize REST to maintain self-renewal of NSCs, 46,48 or prevent hREST4 from ubiquitin-mediated proteasomal degradation to promote neuronal differentiation. 46,49 A dominant negative form of TRF2 triggers a DNA damage response and senescence in mitotic neural cells and TRF2 inhibition enhances the differentiation of hippocampal neurons.…”

Section: Nuclear Role Of Trf2mentioning

confidence: 99%

“…In particular, we and others showed that in the cytoplasm of neurons, TRF2-S binds and stabilizes REST, in turn maintaining the self-renewal of NSCs, 17,48 or binds the truncated, dominant negative isoform hREST4, thus promoting neuronal differentiation. 46,49 In addition, TRF2-S binds and sequesters REST in the cytoplasm of neurons to antagonize REST nuclear activity and to maintain neuronal traits.…”

mentioning

confidence: 99%

The long and the short of TRF2 in neurogenesis

et al. 2016

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Gene expression patterns change dramatically during neuronal development. Proliferating cells, including neural stem cells (NSCs), express telomere repeat-binding factor 2 (TRF2), a nuclear protein that associates with telomeric proteins, DNA, and RNA telomeres. In NSCs TRF2 also binds to the transcription regulator REST to facilitate repression of numerous neuron-specific genes, thereby keeping the NSCs in a selfrenewing state. Upon neuronal differentiation, TRF2 levels decline, REST-regulated neuronal genes are derepressed, and a short isoform of TRF2 arises (TRF2-S) which localizes in the cytoplasm, associates with different subsets of proteins and transcripts, and mobilizes axonal G-rich mRNAs. We recently identified two RNA-binding proteins, HNRNPH1 and H2 (referred to jointly as HNRNPH due to their high homology), which mediate the alternative splicing of an exon required for the expression of full-length TRF2. As HNRNPH levels decline during neurogenesis, TRF2 abundance decreases and TRF2-S accumulates. Here, we discuss the shared and unique functions of TRF2 and TRF2-S, the distinct subcellular compartment in which each isoform resides, the subsets of proteins and nucleic acids with which each interacts, and the functional consequences of these ribonucleoprotein interactions. This paradigm illustrates the dynamic mechanisms through which splicing regulation by factors like HNRNPH enable distinct protein functions as cells adapt to developmental programs such as neurogenesis.

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“…There is another report by Bai et al which showed the role of TRF2 in maintenance of neurospheres in glioblastoma multiforme (GBM) [18].…”

Section: Ivyspringmentioning

confidence: 99%

Role of TRF2 in efficient DNA repair, spheroid formation and Cancer Stem Cell maintenance

Saha¹,

Padhi²,

Kar³

et al. 2017

Oncomedicine

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Chemotherapeutic resistance post-surgical management may be linked to an efficient DNA repair mechanism and survival of cancer stem cells. We report the presence of cancer stem cell like Side Population and their survival and enrichment post treatment with bleomycin in HCT116 cell line. The Side Population exhibited spheroidal characteristics and efficient repair of DNA damage foci compared to the parental HCT-116 cells. We report upregulated expression of β-catenin, TRF2, hTERT, CD44, CD24 and Oct4 genes in parental and clonospheres in a DNA damage environment. Comparative gene expression studies of parental and clonospheric HCT-116 cells revealed significant upregulation (p<0.01) of TRF2 gene in clonospheres. TRF2 which is a Telomere shelterin component is mainly involved in telomere maintenance and DNA repair. We report a role of TRF2 in cancer stem cell maintenance and efficient DNA repair in the clonospheric sub-population of HCT 116 cell line. Silencing of TRF2 gene significantly downregulated β-catenin, CD44, CD24, Oct4 and reduced the size of the clonospheres (4.448μm) when compared to scrambled non-silenced control (11.7273μm). TRF2 Silenced HCT116 parental cells reported compromised DNA repair and 2-fold increase in the number of DSBs as well as γH2Ax foci in the presence of a DSB generating agent Bleomycin, when compared to scrambled non-silenced control. In this study, we confirm a definitive role of TRF2 in stemness of cancer cells and DNA damage response and repair which is an extra-telomeric function and may have therapeutic implications in management of tumor recurrence.

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Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells

Cited by 37 publications

References 64 publications

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

The long and the short of TRF2 in neurogenesis

Role of TRF2 in efficient DNA repair, spheroid formation and Cancer Stem Cell maintenance

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