The Epigenetics of Glioma Stem Cells: A Brief Overview

Valor, Luis M.; Hervás-Corpión, Irati

doi:10.3389/fonc.2020.602378

Cited by 19 publications

(11 citation statements)

References 87 publications

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“…In addition to the lack of consistent mutations affecting the histone H3 genes in TCGA database ( Table S4 ), we should consider in the light of our results that the induction of multiple canonical histone H3 genes in GB impose that rare mutations may only affect a small fraction of the total H3.1/H3.2 proteins. In contrast, mutations in the H3-3A gene are highly relevant in pediatric GB but they have a dominant-negative effect, while the reduction of the protein levels in adult H3-3A wild-type GB indicated a loss of function [ 23 , 51 ]; in the few adult cases with the mutated gene [ 52 ], it will be interesting to elucidate whether both mechanisms of H3.3 dysfunction coexist. Therefore, the impact of such variations should be clarified.…”

Section: Discussionmentioning

confidence: 99%

Potential Diagnostic Value of the Differential Expression of Histone H3 Variants between Low- and High-Grade Gliomas

Hervás-Corpión

Gallardo-Orihuela

Catalina-Fernández

et al. 2021

Cancers

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Glioblastoma (GB) is the most aggressive form of glioma and is characterized by poor prognosis and high recurrence despite intensive clinical interventions. To retrieve the key factors underlying the high malignancy of GB with potential diagnosis utility, we combined the analysis of The Cancer Gene Atlas and the REMBRANDT datasets plus a molecular examination of our own collection of surgical tumor resections. We determined a net reduction in the levels of the non-canonical histone H3 variant H3.3 in GB compared to lower-grade astrocytomas and oligodendrogliomas with a concomitant increase in the levels of the canonical histone H3 variants H3.1/H3.2. This increase can be potentially useful in the clinical diagnosis of high-grade gliomas, as evidenced by an immunohistochemistry screening of our cohort and can be at least partially explained by the induction of multiple histone genes encoding these canonical forms. Moreover, GBs showing low bulk levels of the H3.1/H3.2 proteins were more transcriptionally similar to low-grade gliomas than GBs showing high levels of H3.1/H3.2. In conclusion, this study identifies an imbalanced ratio between the H3 variants associated with glioma malignancy and molecular patterns relevant to the biology of gliomas, and proposes the examination of the H3.3 and H3.1/H3.2 levels to further refine diagnosis of low- and high-grade gliomas in future studies.

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Section: Discussionmentioning

confidence: 99%

Potential Diagnostic Value of the Differential Expression of Histone H3 Variants between Low- and High-Grade Gliomas

Hervás-Corpión

Gallardo-Orihuela

Catalina-Fernández

et al. 2021

Cancers

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“…The methylome of tumors has been integrated in most heterogeneity papers using high-throughput methods, especially for temporal heterogeneity studies. DNA methylation has also advanced the knowledge in intra-tumor spatial heterogeneity, especially in the characterization of CSCs and inflammatory cells [ 78 , 79 , 80 , 81 ]. Notably, differences in DNA methylation between tumor areas as close as 5 mm apart were observed, both in IDH mutant and IDH wild-type gliomas [ 64 ].…”

Section: Reviewmentioning

confidence: 99%

“…Overexpression of EZH2 in HGGs is associated with worse OS. This gene is part of the polycomb repressive complexes involved in the epigenetic modulation of GSCs, the most studied epigenetic modulators in GSCs, and is therefore a potential therapeutic target [ 80 ].…”

Section: Reviewmentioning

confidence: 99%

Tumor Heterogeneity in Glioblastomas: From Light Microscopy to Molecular Pathology

Becker

Sells

Haque

et al. 2021

Cancers

119

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One of the main reasons for the aggressive behavior of glioblastoma (GBM) is its intrinsic intra-tumor heterogeneity, characterized by the presence of clonal and subclonal differentiated tumor cell populations, glioma stem cells, and components of the tumor microenvironment, which affect multiple hallmark cellular functions in cancer. “Tumor Heterogeneity” usually encompasses both inter-tumor heterogeneity (population-level differences); and intra-tumor heterogeneity (differences within individual tumors). Tumor heterogeneity may be assessed in a single time point (spatial heterogeneity) or along the clinical evolution of GBM (longitudinal heterogeneity). Molecular methods may detect clonal and subclonal alterations to describe tumor evolution, even when samples from multiple areas are collected in the same time point (spatial-temporal heterogeneity). In GBM, although the inter-tumor mutational landscape is relatively homogeneous, intra-tumor heterogeneity is a striking feature of this tumor. In this review, we will address briefly the inter-tumor heterogeneity of the CNS tumors that yielded the current glioma classification. Next, we will take a deeper dive in the intra-tumor heterogeneity of GBMs, which directly affects prognosis and response to treatment. Our approach aims to follow technological developments, allowing for characterization of intra-tumor heterogeneity, beginning with differences on histomorphology of GBM and ending with molecular alterations observed at single-cell level.

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“…One of the major reasons for poor prognosis is glioma stem cells (GSCs) [3]. GSCs are characterized by high expression of the stem cell markers CD133, Nestin and Sox2 and extensive self-renewal and multilineage differentiation potentials [3][4][5]. Recent studies found that the initiation, progression, metastasis and recurrence of gliomas were mainly driven by GSCs [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling

Ren

Zhao

et al. 2021

Int. J. Biol. Sci.

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Rationale:The malignant phenotypes of glioblastomas (GBMs) are primarily attributed to glioma stem cells (GSCs). Our previous study and other reports have suggested that both miR-139 and its host gene PDE2A are putative antitumor genes in various cancers. The aim of this study was to investigate the roles and mechanisms of miR-139/PDE2A in GSC modulation. Methods: Clinical samples were used to determine miR-139/PDE2A expression. Patient-derived glioma stem-like cells (PD-GSCs) were stimulated for immunofluorescent staining, sphere formation assays and orthotopic GBM xenograft models. Bioinformatic analysis and further in vitro experiments demonstrated the downstream molecular mechanisms of miR-139 and PDE2A. OX26/CTX-conjugated PEGylated liposome (OCP) was constructed to deliver miR-139 or PDE2A into glioma tissue specifically. Results: We demonstrated that miR-139 was concomitantly transcribed with its host gene PDE2A. Both PDE2A and miR-139 indicated better prognosis of gliomas and were inversely correlated with GSC stemness. PDE2A or miR-139 overexpression suppressed the stemness of PD-GSCs. FZD3 and β-catenin, which induced Wnt/β-catenin signaling activation, were identified as targets of miR-139 and mediated the effects of miR-139 on GSCs. Meanwhile, PDE2A suppressed Wnt/β-catenin signaling by inhibiting cAMP accumulation and GSK-3β phosphorylation, thereby modulating the self-renewal of PD-GSCs. Notably, Notch1, which is also a target of miR-139, suppressed PDE2A/miR-139 expression directly via downstream Hes1, indicating that miR-139 promoted its own expression by the miR-139-Notch1/Hes1 feedback circuit. Expectedly, targeted overexpression miR-139 or PDE2A in glioma with OCP system significantly repressed the stemness and decelerated glioma progression. Conclusions: Our findings elaborate on the inhibitory functions of PDE2A and miR-139 on GSC stemness and tumorigenesis, which may provide new prognostic markers and therapeutic targets for GBMs.

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The Epigenetics of Glioma Stem Cells: A Brief Overview

Cited by 19 publications

References 87 publications

Potential Diagnostic Value of the Differential Expression of Histone H3 Variants between Low- and High-Grade Gliomas

Potential Diagnostic Value of the Differential Expression of Histone H3 Variants between Low- and High-Grade Gliomas

Tumor Heterogeneity in Glioblastomas: From Light Microscopy to Molecular Pathology

miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling

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