Id4 suppresses MMP2-mediated invasion of glioblastoma-derived cells by direct inactivation of Twist1 function

Rahme, Gilbert J.; Israel, Mark A.

doi:10.1038/onc.2013.531

Cited by 56 publications

(56 citation statements)

References 56 publications

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“…The antibodies used and the working dilutions are shown in Supplementary Table S1. Antibodies that recognize ID proteins were validated in a previous report from our laboratory (33).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Western blot analysis was done as described previously (33). The antibodies used and the working dilutions are shown in Supplementary Table S1.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Chromatin immunoprecipitation (ChIP) was performed as described previously (33). Data were analyzed using the 2 ÀDDCt method with normalization to the IgG isotype control ChIP of cells that were treated in a manner identical to the experimental cells.…”

Section: Chromatin Immunoprecipitation Analysismentioning

confidence: 99%

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PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells

et al. 2016

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Glioblastoma is the most aggressive primary brain tumor and responds poorly to currently available therapies. Transcriptomic characterization of glioblastoma has identified distinct molecular subtypes of glioblastoma. Gain-of-function alterations leading to enhanced platelet-derived growth factor (PDGF) signaling are commonly observed in the proneural subtype of glioblastoma and can drive gliomagenesis. However, little is known about the downstream effectors of PDGF signaling in glioblastoma. Using a mouse model of proneural glioma and comparative transcriptomics, we determined that PDGF signaling upregulated ubiquitin-specific peptidase 1 (Usp1) to promote the survival of murine proneural glioma cells. Mechanistically, we found that PDGF signaling regulated the expression of the E2F transcription factors, which directly bound to and activated Usp1. Furthermore, PDGF-mediated expression of USP1 led to the stabilization of Inhibitor of DNA-binding 2 (ID2), which we found to be required for glioma cell survival. Genetic ablation of Id2 delayed tumor-induced mortality, and pharmacologic inhibition of USP1, resulting in decreased ID2 levels, also delayed tumorigenesis in mice. Notably, decreased USP1 expression was associated with prolonged survival in patients with proneural glioblastoma, but not with other subtypes of glioblastoma. Collectively, our findings describe a signaling cascade downstream of PDGF that sustains proneural glioblastoma cells and suggest that inhibition of the PDGF-E2F-USP1-ID2 axis could serve as a therapeutic strategy for proneural glioblastoma featuring increased PDGF signaling.

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“…The antibodies used and the working dilutions are shown in Supplementary Table S1. Antibodies that recognize ID proteins were validated in a previous report from our laboratory (33).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Western blot analysis was done as described previously (33). The antibodies used and the working dilutions are shown in Supplementary Table S1.…”

Section: Western Blot Analysismentioning

confidence: 99%

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PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells

et al. 2016

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“…The activity of MMPs is highly regulated under normal conditions because they are involved in many physiological processes such as tissue remodelling, angiogenesis, wound healing, embryogenesis, nerve growth and apoptosis (Rahme et al, 2015). In contrast, MMPs are overexpressed and unregulated in pathological conditions such as cancer and cardiovascular diseases (Nagase and Woessner, 1999).…”

Section: Matrix Metalloproteinasesmentioning

confidence: 99%

“…Furthermore, immunohistochemical technique showed the localisation of MMP2 and MMP9 in only glioma cells and its blood vessels (Sawaya et al, 1996;Ramachandran et al, 2017). MMP2 was highly expressed in GBM tissue samples as well as all transformed cell lines but not in healthy brain tissues (Deshane et al, 2003;Kargiotis et al, 2008;Hagemann et al, 2010;Rahme et al, 2015).…”

Section: High Expression Of Mmp2 Mmp9 and Annexin A2 In Gbmmentioning

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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Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma

et al. 2018

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TWIST1 (TW) is a bHLH transcription factor (TF) and master regulator of the epithelial‐to‐mesenchymal transition (EMT). In vitro, TW promotes mesenchymal change, invasion, and self‐renewal in glioblastoma (GBM) cells. However, the potential therapeutic relevance of TW has not been established through loss‐of‐function studies in human GBM cell xenograft models. The effects of TW loss of function (gene editing and knockdown) on inhibition of tumorigenicity of U87MG and GBM4 glioma stem cells were tested in orthotopic xenograft models and conditional knockdown in established flank xenograft tumors. RNAseq and the analysis of tumors investigated putative TW‐associated mechanisms. Multiple bioinformatic tools revealed significant alteration of ECM, membrane receptors, signaling transduction kinases, and cytoskeleton dynamics leading to identification of PI3K/AKT signaling. We experimentally show alteration of AKT activity and periostin (POSTN) expression in vivo and/or in vitro. For the first time, we show that effect of TW knockout inhibits AKT activity in U87MG cells in vivo independent of PTEN mutation. The clinical relevance of TW and candidate mechanisms was established by analysis of the TCGA and ENCODE databases. TW expression was associated with decreased patient survival and LASSO regression analysis identified POSTN as one of top targets of TW in human GBM. While we previously demonstrated the role of TW in promoting EMT and invasion of glioma cells, these studies provide direct experimental evidence supporting protumorigenic role of TW independent of invasion in vivo and the therapeutic relevance of targeting TW in human GBM. Further, the role of TW driving POSTN expression and AKT signaling suggests actionable targets, which could be leveraged to mitigate the oncogenic effects of TW in GBM.

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Id4 suppresses MMP2-mediated invasion of glioblastoma-derived cells by direct inactivation of Twist1 function

Cited by 56 publications

References 56 publications

PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells

PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells

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

Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma

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