Bmi1 regulates human glioblastoma stem cells through activation of differential gene networks in CD133+ brain tumor initiating cells

Vora, Parvez; Seyfrid, Mathieu; Venugopal, Chitra; Qazi, Maleeha; Salim, Sabra K.; Isserlin, Ruth; Subapanditha, Minomi; O’Farrell, Erin; Mahendram, Sujeivan; Singh, Mohini; Bakhshinyan, David; Chokshi, Chirayu; McFarlane, Nicole; Dvorkin‐Gheva, Anna; Brown, Kevin R.; Murty, Naresh K.; Moffat, Jason; Bader, Gary D.; Singh, Sheila K.

doi:10.1007/s11060-019-03192-1

Cited by 17 publications

(12 citation statements)

References 63 publications

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“…Human GBM samples were obtained from consenting patients, as approved by the Hamilton Health Sciences/McMaster Health Sciences Research Ethics Board. Brain tumor samples were dissociated as previously described [17] and cultured as neurospheres in Neurocult complete (NCC) media, a chemically defined serum-free neural stem cell medium (STEMCELL Technologies, Vancouver, Canada), supplemented with human recombinant epidermal growth factor (20 ng/mL: STEMCELL Technologies, Vancouver, Canada), basic fibroblast growth factor (20 ng/mL; STEMCELL Technologies, Vancouver, Canada), heparin (2 µg/mL 0.2% Heparin Sodium Salt in PBS; STEMCELL technologies, Vancouver, Canada), antibiotic-antimycotic (10 mg/mL; Wisent Bioproducts, Quebec, Canada) in ultra-low attachment plates (Corning, New York, USA). Primary GBM cells (BT 428, BT 458 and BT 624) were cultured in NSC complete media and flow-sorted for CD133+ and CD133-populations as described previously [18,19].…”

Section: Dissociation and Culture Of Primary Gbm Tissuementioning

confidence: 99%

ETS-Domain Transcription Factor Elk-1 Regulates Stemness Genes in Brain Tumors and CD133+ BrainTumor-Initiating Cells

Söğüt

Venugopal

Kandemir

et al. 2021

JPM

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Elk-1, a member of the ternary complex factors (TCFs) within the ETS (E26 transformation-specific) domain superfamily, is a transcription factor implicated in neuroprotection, neurodegeneration, and brain tumor proliferation. Except for known targets, c-fos and egr-1, few targets of Elk-1 have been identified. Interestingly, SMN, SOD1, and PSEN1 promoters were shown to be regulated by Elk-1. On the other hand, Elk-1 was shown to regulate the CD133 gene, which is highly expressed in brain-tumor-initiating cells (BTICs) and used as a marker for separating this cancer stem cell population. In this study, we have carried out microarray analysis in SH-SY5Y cells overexpressing Elk-1-VP16, which has revealed a large number of genes significantly regulated by Elk-1 that function in nervous system development, embryonic development, pluripotency, apoptosis, survival, and proliferation. Among these, we have shown that genes related to pluripotency, such as Sox2, Nanog, and Oct4, were indeed regulated by Elk-1, and in the context of brain tumors, we further showed that Elk-1 overexpression in CD133+ BTIC population results in the upregulation of these genes. When Elk-1 expression is silenced, the expression of these stemness genes is decreased. We propose that Elk-1 is a transcription factor upstream of these genes, regulating the self-renewal of CD133+ BTICs.

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Section: Dissociation and Culture Of Primary Gbm Tissuementioning

confidence: 99%

ETS-Domain Transcription Factor Elk-1 Regulates Stemness Genes in Brain Tumors and CD133+ BrainTumor-Initiating Cells

Söğüt

Venugopal

Kandemir

et al. 2021

JPM

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“…Due to the great variation in the transfection efficiency of GSCs from different patients, U87 glioma cells were used to isolate GSCs to obtain homogeneity. Previous data have suggested several cell markers for GSCs; among them, CD133 + cells in glioblastoma display cancer stem cell-like properties and CD133 is known to be highly expressed in GSCs (15,56). However, more rigorous research will be required to establish whether CD133 is an effective marker of GSCs.…”

Section: Discussionmentioning

confidence: 99%

GASC1 promotes glioma progression by enhancing NOTCH1 signaling

et al. 2021

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Recent studies have reported that gene amplified in squamous cell carcinoma 1 (GASC1) is involved in the progression of several types of cancer. However, whether GASC1 promotes glioma progression remains unknown. Therefore, the present study aimed to investigate the effect of GASC1 exposure on glioma tumorigenesis. The western blot demonstrated that grade III and IV glioma tissues exhibited a higher mRNA and protein expression of GASC1. Moreover, CD133 + U87 or U251 cells from magnetic cell separation exhibited a higher GASC1 expression. Invasion Transwell assay, clonogenic assay and wound healing assay have shown that GASC1 inhibition using a pharmacological inhibitor and specific short hairpin (sh)RNA suppressed the invasive, migratory and tumorsphere forming abilities of primary culture human glioma cells. Furthermore, GASC1-knockdown decreased notch receptor (Notch) responsive protein hes family bHLH transcription factor 1 (Hes1) signaling. GASC1 inhibition reduced notch receptor 1 (NOTCH1) expression, and a NOTCH1 inhibitor enhanced the effects of GASC1 inhibition on the CD133 + U87 or U251 cell tumorsphere forming ability, while NOTCH1 overexpression abrogated these effects. In addition, the GASC1 inhibitor caffeic acid and/or the NOTCH1 inhibitor DAPT (a γ-Secretase Inhibitor), efficiently suppressed the human glioma xenograft tumors. Thus, the present results demonstrated the importance of GASC1 in the progression of glioma and identified that GASC1 promotes glioma progression, at least in part, by enhancing NOTCH signaling, suggesting that GASC1/NOTCH1 signaling may be a potential therapeutic target for glioma treatment.

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“…Further disruption of parallel epigenetic and chromatin remodeling pathways could cause further erosion and induce complete loss of self-renewal and the attainment of a terminally differentiated phenotype. As such, treatment strategies that target epigenetic networks of stemness could be successful against cancer stem cells in these lethal cancers (Gallo et al, 2015;Lan et al, 2017;Vora et al, 2019). There is also evidence that chromatin states associated with self-renewal result in specific 3D genome architecture.…”

Section: Can a Tumor Be Driven Uniquely By Epigenetic Mechanisms?mentioning

confidence: 99%

Dysregulation of chromatin organization in pediatric and adult brain tumors: oncoepigenomic contributions to tumorigenesis and cancer stem cell properties

Paik

Maule

Gallo

2021

Genome

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The three-dimensional (3D) organization of the genome is a crucial enabler of cell fate, identity and function. In this review, we will focus on the emerging role of altered 3D genome organization in the etiology of disease, with a special emphasis on brain cancers. We discuss how different genetic alterations can converge to disrupt the epigenome in childhood and adult brain tumors, by causing aberrant DNA methylation and by affecting the amounts and genomic distribution of histone post-translational modifications. We also highlight examples that illustrate how epigenomic alterations have the potential to affect 3D genome architecture in brain tumors. Finally, we will propose the concept of “epigenomic erosion” to explain the transition from stem-like cells to differentiated cells in hierarchically-organized brain cancers.

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Bmi1 regulates human glioblastoma stem cells through activation of differential gene networks in CD133+ brain tumor initiating cells

Cited by 17 publications

References 63 publications

ETS-Domain Transcription Factor Elk-1 Regulates Stemness Genes in Brain Tumors and CD133+ BrainTumor-Initiating Cells

ETS-Domain Transcription Factor Elk-1 Regulates Stemness Genes in Brain Tumors and CD133+ BrainTumor-Initiating Cells

GASC1 promotes glioma progression by enhancing NOTCH1 signaling

Dysregulation of chromatin organization in pediatric and adult brain tumors: oncoepigenomic contributions to tumorigenesis and cancer stem cell properties

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