Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma

Kling, Teresia; Ferrarese, Roberto; hAilín, Darren Ó.; Johansson, Patrik; Heiland, Dieter Henrik; Dai, Fangping; Vasilikos, Ioannis; Weyerbrock, Astrid; Jörnsten, Rebecka; Carro, Maria Stella; Nelander, Sven

doi:10.1016/j.ebiom.2016.08.050

Cited by 27 publications

(31 citation statements)

References 54 publications

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“…Promoter methylation analysis of the subset of gliomas with low ZBTB18 expression/high promoter methylation (indicated in red) vs. high ZBTB18 expression/low promoter methylation (indicated in blue) previously analyzed using the Infinium HumanMethylation450 BeadChip [45] (Supplementary Figure S7D) confirmed differential methylation of CpG island 2 between the two tumor groups covering CpGs located in the same region analyzed by pyrosequencing (probes cg19698993 and cg12869659). Intriguingly, tumor samples with high ZBTB18 expression and low ZBTB18 promoter methylation analyzed by DNA methylation array showed high levels of global methylation [45], suggesting that silencing of ZBTB18 by promoter methylation could be a hallmark of non G-CIMP gliomas.…”

Section: Resultsmentioning

confidence: 73%

“…Intriguingly, tumor samples with high ZBTB18 expression and low ZBTB18 promoter methylation analyzed by DNA methylation array showed high levels of global methylation [45], suggesting that silencing of ZBTB18 by promoter methylation could be a hallmark of non G-CIMP gliomas. Consistent with this hypothesis, ZBTB18 methylation correlated with G-CIMP and IDH1 mutation status so that ZBTB18 was more methylated in IDH1 wild type compared to IDH1 mutant gliomas (Figure 7C p= 1.914e-10, Welch Two Sample t-test).…”

Section: Resultsmentioning

confidence: 99%

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Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

Fedele

Dai

Masilamani

et al. 2017

Molecular Cancer Research

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Glioblastoma (GBM) is comprised of distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation. Here, ZBTB18 is primarily silenced in the mesenchymal subtype of GBM through aberrant promoter methylation. Loss of ZBTB18 contributes to the aggressive phenotype of glioblastoma through regulation of poor prognosis-associated signatures. Restitution of ZBTB18 expression reverses the phenotype and impairs tumor-forming ability. These results indicate that ZBTB18 functions as a tumor suppressor in GBM through the regulation of genes associated with phenotypically aggressive properties. Implications This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass.

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Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

Fedele

Dai

Masilamani

et al. 2017

Molecular Cancer Research

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“…STAT3 assists in GBM cell invasion by inducing SNAI1 and activation of MMPs (Priester et al, 2013). Recent work suggests that mesenchymal transformation by STAT3 is controlled through Annexin-A2 (ANXA2) that is inactivated in GBMs that exhibit mutations in the isocitrate dehydrogenase (IDH) gene (Kling et al, 2016).…”

Section: Regulators Of Mt and Gbm Progressionmentioning

confidence: 99%

“…Promoter methylation is another important mechanism for the control of gene transcription and EMT regulation. Recent evidences occurred showing that expression of ANXA2, an inducer of mesenchymal transformation, is suppressed by promoter hypermethylation and is associated with a better prognosis in CpG hypermethylator phenotype (GCIMP) GBM (Kling et al, 2016).…”

Section: Epigenetic Regulation Of Mt and Long Noncoding Rnasmentioning

confidence: 99%

EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

2017

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The epithelial‐to mesenchymal (EMT) process is increasingly recognized for playing a key role in the progression, dissemination, and therapy resistance of epithelial tumors. Accumulating evidence suggests that EMT inducers also lead to a gain in mesenchymal properties and promote malignancy of nonepithelial tumors. In this review, we present and discuss current findings, illustrating the importance of EMT inducers in tumors originating from nonepithelial/mesenchymal tissues, including brain tumors, hematopoietic malignancies, and sarcomas. Among these tumors, the involvement of mesenchymal transition has been most extensively investigated in glioblastoma, providing proof for cell autonomous and microenvironment‐derived stimuli that provoke EMT‐like processes that regulate stem cell, invasive, and immunogenic properties as well as therapy resistance. The involvement of prominent EMT transcription factor families, such as TWIST, SNAI, and ZEB, in promoting therapy resistance and tumor aggressiveness has also been reported in lymphomas, leukemias, and sarcomas. A reverse process, resembling mesenchymal‐to‐epithelial transition (MET), seems particularly relevant for sarcomas, where (partial) epithelial differentiation is linked to less aggressive tumors and a better patient prognosis. Overall, a hybrid model in which more stable epithelial and mesenchymal intermediates exist likely extends to the biology of tumors originating from sources other than the epithelium. Deeper investigation and understanding of the EMT/MET machinery in nonepithelial tumors will shed light on the pathogenesis of these tumors, potentially paving the way toward the identification of clinically relevant biomarkers for prognosis and future therapeutic targets.

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“…The N-terminal domain is involved in the tPA binding site whereas, the C-terminal domain is involved in calcium binding as well as phospholipid binding and F-actin binding (Jones et al, 1992;Rety et al, 1999). MMP2 and AnxA2 are potential candidates for molecular targeted therapy for glioma because they are involved in GBM invasion, adhesion, angiogenesis and metastasis (Kling et al, 2016). GBM is resistant to surgery and chemotherapy due to its diffuse nature (Ramirez et al, 2013).…”

Section: Structure Of Annexin A2mentioning

confidence: 99%

The mechanism of action of the scorpion toxin, chlorotoxin, a bioinformatics approach

Sheikh¹

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Glioblastoma is a very invasive and metastatic cancer with low patient survival-rate and high resistance to current treatment. Matrix metalloproteinase 2 (MMP2) is upregulated in glioblastoma multiforme (GBM) and its high expression is directly correlated with invasion and metastasis of GBM cells. Annexin A2 is involved in angiogenesis, and it is overexpressed in GBM. MMP2 and annexin A2 are potential targets for effective glioma therapy. Chlorotoxin is a promising toxin peptide for glioma targeted therapy. Chlorotoxin decreased migration and metastasis of GBM cells, although mechanism of action of the toxin is unclear due to the complicated nature of GBM, slow and costly experiments and challenging techniques. The relationship of chlorotoxin binding to both MMP2 and annexin A2 is controversial and further work is needed to clarify a complex situation. Chlorotoxin-like short toxins are homologous peptides that may also have potential therapeutic effects for glioma.In this study homology modelling was used to predict 3D models of chlorotoxin-like short toxins. Stereochemical quality estimation of 3D models was performed with QMEAN, Z-Score and Procheck server. ClusPro docking programme was used to dock 3D structures of chlorotoxin and chlorotoxin homologues with their putative binding partners MMP2 and annexin A2 to provide a first step to understand the mechanism of action of the toxin. Chlorotoxin shows binding interaction with both MMP2 and annexin A2. Chlorotoxin-like short toxins also showed stronger binding interaction with activated MMP2 than annexin A2. The positively charged surface of chlorotoxin is mainly involved in interaction with MMP2. All three chlorotoxin-like short toxins bind to a similar site on MMP2 but on separate sites on annexin A2hence suggesting the significance of observed interaction between chlorotoxin and MMP2.

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Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma

Cited by 27 publications

References 54 publications

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

The mechanism of action of the scorpion toxin, chlorotoxin, a bioinformatics approach

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