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Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma.

ABSTRACT: Glioblastoma (GBM) is the most common and most aggressive intrinsic brain tumour in adults. Integrated transcriptomic and epigenomic analyses of glioblastoma initiating cells (GIC) in a mouse model uncovered a novel epigenetic regulation of EfnA5. In this model, Bmi1 enhances H3K27me3 at the EfnA5 locus and reinforces repression of selected target genes in a cellular context-dependent fashion. EfnA5 mediates Bmi1-dependent proliferation and invasion in vitro and tumour formation in an allograft model. Importantly, we show that this novel Polycomb feed-forward loop is also active in human GIC and we provide pre-clinical evidence of druggability of the EFNA5 signalling pathway in GBM xenografts overexpressing Bmi1.

SUBMITTER: Ricci B

PROVIDER: S-EPMC7082224 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma.

Ricci Barbara B Millner Thomas O TO Pomella Nicola N Zhang Xinyu X Guglielmi Loredana L Badodi Sara S Ceric Dario D Gemma Carolina C Cognolato Erica E Zhang Ying Y Brandner Sebastian S Barnes Michael R MR Marino Silvia S

Oncogene 20200127 12

Glioblastoma (GBM) is the most common and most aggressive intrinsic brain tumour in adults. Integrated transcriptomic and epigenomic analyses of glioblastoma initiating cells (GIC) in a mouse model uncovered a novel epigenetic regulation of EfnA5. In this model, Bmi1 enhances H3K27me3 at the EfnA5 locus and reinforces repression of selected target genes in a cellular context-dependent fashion. EfnA5 mediates Bmi1-dependent proliferation and invasion in vitro and tumour formation in an allograft ...[more]

PMID: 31988455

Similar Datasets

Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma

Project description:Glioblastoma (GBM) is the most common and most aggressive intrinsic brain tumour in adults. Integrated transcriptomic and epigenomic analyses of glioblastoma initiating cells (GIC) in a mouse model uncovered a novel epigenetic regulation of EfnA5. In this model, Bmi1 enhances H3K27me3 at the EfnA5 locus and reinforces repression of selected target genes in a cellular context dependent fashion. EfnA5 mediate Bmi1-dependent proliferation and invasion in vitro and tumour formation in an allograft model. Importantly, we show that this novel Polycomb feed-forward loop is also active in human GIC and we provide preclinical evidence of druggability of EFNA5 in GBM xenografts overexpressing BMI1.

2020-02-01 | GSE141961 | GEO

Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma

Project description:Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma

| PRJNA595392 | ENA

Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness.

Project description:MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR-based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of non-canonical Polycomb ncPRC1.6 targets, including genes involved in metastasis and meiosis. Moreover, MGA deletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes these ncPRC1.6 subunits. Lastly, we report that MGA loss also induces a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F target genes mediated by MGA-MAX associated with a non-canonical Polycomb complex.

| S-EPMC8266391 | biostudies-literature

Suppression of lung adenocarcinoma through menin and polycomb gene-mediated repression of growth factor pleiotrophin.

Project description:Menin upregulates transcription of cell-cycle inhibitors to suppress endocrine tumors, but it is poorly understood how menin suppresses non-endocrine tumors such as lung cancer. Here, we show that menin inhibits proliferation of human lung cancer cells and growth of lung cancer in mice. The menin-mediated tumor suppression requires repression of growth factor pleiotrophin (PTN), which binds to its cell surface receptor, anaplastic lymphoma kinase (ALK) that is activated in certain lung adenocarcinomas. Menin represses PTN transcription and PTN-induced proliferation of human lung cancer cells, and menin expression is substantially reduced in primary human lung adenocarcinomas. Notably, menin binds the PTN locus and enhances Polycomb gene Enhancer of Zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27m3), a negative mark for gene transcription but does not affect histone H3K4 methylation that is usually upregulated by menin in endocrine cells. Together, our findings indicate that menin suppresses lung cancer partly through increasing Polycomb gene-mediated H3K27 methylation and repressing PTN transcription, unraveling a novel, epigenetically regulated PTN-ALK signaling pathway in suppressing lung cancer.

| S-EPMC5399538 | biostudies-literature

Polycomb group protein EZH2-mediated E-cadherin repression promotes metastasis of oral tongue squamous cell carcinoma.

Project description:Enhancer of Zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2) that regulates many essential biological processes, including embryogenesis and many developmental events. The oncogenic role of EZH2 has recently been implicated in several cancer types. In this study, we first confirmed that the over-expression of EZH2 is a frequent event in oral tongue squamous cell carcinoma (OTSCC). We further demonstrated that EZH2 over-expression is correlated with advanced stages of the disease and is associated with lymph node metastasis. Statistical analysis revealed that EZH2 over-expression was correlated with reduced overall survival. Furthermore, over-expression of EZH2 was correlated with reduced expression of tumor suppressor gene E-cadherin. These observations were confirmed in vitro, in which knockdown of EZH2-induced E-cadherin expression and reduced cell migration and invasion. In contrast, ectopic transfection of EZH2 led to reduced E-cadherin expression and enhanced cell migration and invasion. Furthermore, EZH2 may act on cell migration in part by suppressing the E-cadherin expression. Taken together, these data suggest that EZH2 plays major roles in the progression of OTSCC, and may serve as a biomarker or therapeutic target for patients at risk of metastasis.

| S-EPMC3400713 | biostudies-literature

α2,6 Sialylation mediated by ST6GAL1 promotes glioblastoma growth.

Project description:One of the least-investigated areas of brain pathology research is glycosylation, which is a critical regulator of cell surface protein structure and function. β-Galactoside α2,6-sialyltransferase (ST6GAL1) is the primary enzyme that α2,6 sialylates N-glycosylated proteins destined for the plasma membrane or secretion, thereby modulating cell signaling and behavior. We demonstrate a potentially novel, protumorigenic role for α2,6 sialylation and ST6GAL1 in the deadly brain tumor glioblastoma (GBM). GBM cells with high α2,6 sialylation exhibited increased in vitro growth and self-renewal capacity and decreased mouse survival when orthotopically injected. α2,6 Sialylation was regulated by ST6GAL1 in GBM, and ST6GAL1 was elevated in brain tumor-initiating cells (BTICs). Knockdown of ST6GAL1 in BTICs decreased in vitro growth, self-renewal capacity, and tumorigenic potential. ST6GAL1 regulates levels of the known BTIC regulators PDGF Receptor β (PDGFRB), Activated Leukocyte Cell Adhesion Molecule, and Neuropilin, which were confirmed to bind to a lectin-recognizing α2,6 sialic acid. Loss of ST6GAL1 was confirmed to decrease PDGFRB α2,6 sialylation, total protein levels, and the induction of phosphorylation by PDGF-BB. Thus, ST6GAL1-mediated α2,6 sialylation of a select subset of cell surface receptors, including PDGFRB, increases GBM growth.

| S-EPMC9675560 | biostudies-literature

RBM8A Promotes Glioblastoma Growth and Invasion Through the Notch/STAT3 Pathway.

Project description:BackgroundGlioblastoma (GBM) is a prevalent brain malignancy with an extremely poor prognosis, which is attributable to its invasive biological behavior. The RNA-binding motif protein 8A (RBM8A) has different effects on various human cancers. However, the role of RBM8A in GBM progression remains unclear.MethodsWe investigated the expression levels of RBM8A in 94 GBM patients and explored the correlation between RBM8A expression and patient prognosis. Using in vitro and in vivo assays, combined with GBM sequencing data from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we examined whether and how RBM8A contributes to GBM progression.ResultsRBM8A was up-regulated in GBM tissues, and its higher expression correlated with worse prognosis. Knockdown of RBM8A inhibited GBM progression and invasion ability both in vitro and in vivo. On the contrary, overexpression of RBM8A promoted GBM progression and invasion ability. Enrichment analysis of differentially expressed genes in GBM data identified the Notch1/STAT3 network as a potential downstream target of RBM8A, and this was supported by molecular docking studies. Furthermore, we demonstrated that RBM8A regulates the transcriptional activity of CBF1. The γ-secretase inhibitor DAPT significantly reversed RBM8A-enhanced GBM cell proliferation and invasion, and was associated with down-regulation of p-STAT3 and Notch1 protein. Finally, the gene set variance analysis score of genes involved in regulation of the Notch1/STAT3 network by RBM8A showed good diagnostic and prognostic value for GBM.ConclusionsRBM8A may promote GBM cell proliferation and migration by activating the Notch/STAT3 pathway in GBM cells, suggesting that RBM8A may serve as a potential therapeutic target for the treatment of GBM.

| S-EPMC8600138 | biostudies-literature

PRL1 Promotes Glioblastoma Invasion and Tumorigenesis via Activating USP36-Mediated Snail2 Deubiquitination

Project description:Regenerating liver phosphatase 1 (PRL1) is an established oncogene in various cancers, although its biological function and the underlying mechanisms in glioblastoma multiforme (GBM) remain unclear. Here, we showed that PRL1 was significantly upregulated in glioma tissues and cell lines, and positively correlated with the tumor grade. Consistently, ectopic expression of PRL1 in glioma cell lines significantly enhanced their tumorigenicity and invasion both in vitro and in vivo by promoting epithelial-mesenchymal transition (EMT). Conversely, knocking down PRL1 blocked EMT in GBM cells, and inhibited their invasion, migration and tumorigenic growth. Additionally, PRL1 also stabilized Snail2 through its deubiquitination by activating USP36, thus revealing Snail2 as a crucial mediator of the oncogenic effects of PRL1 in GBM pathogenesis. Finally, PRL1 protein levels were positively correlated with that of Snail2 and predicted poor outcome of GBMs. Collectively, our data support that PRL1 promotes GBM progression by activating USP36-mediated Snail2 deubiquitination. This novel PRL1/USP36/Snail2 axis may be a promising therapeutic target for glioblastoma.

| S-EPMC8801937 | biostudies-literature

Synergy between Variant PRC1 Complexes Defines Polycomb-Mediated Gene Repression.

Project description:The Polycomb system modifies chromatin and plays an essential role in repressing gene expression to control normal mammalian development. However, the components and mechanisms that define how Polycomb protein complexes achieve this remain enigmatic. Here, we use combinatorial genetic perturbation coupled with quantitative genomics to discover the central determinants of Polycomb-mediated gene repression in mouse embryonic stem cells. We demonstrate that canonical Polycomb repressive complex 1 (PRC1), which mediates higher-order chromatin structures, contributes little to gene repression. Instead, we uncover an unexpectedly high degree of synergy between variant PRC1 complexes, which is fundamental to gene repression. We further demonstrate that variant PRC1 complexes are responsible for distinct pools of H2A monoubiquitylation that are associated with repression of Polycomb target genes and silencing during X chromosome inactivation. Together, these discoveries reveal a new variant PRC1-dependent logic for Polycomb-mediated gene repression.

| S-EPMC6561741 | biostudies-literature

Histone H2AK119 Mono-Ubiquitination Is Essential for Polycomb-Mediated Transcriptional Repression.

Project description:Polycomb group proteins (PcGs) maintain transcriptional repression to preserve cellular identity in two distinct repressive complexes, PRC1 and PRC2, that modify histones by depositing H2AK119ub1 and H3K27me3, respectively. PRC1 and PRC2 exist in different variants and show a complex regulatory cross-talk. However, the contribution that H2AK119ub1 plays in mediating PcG repressive functions remains largely controversial. Using a fully catalytic inactive RING1B mutant, we demonstrated that H2AK119ub1 deposition is essential to maintain PcG-target gene repression in embryonic stem cells (ESCs). Loss of H2AK119ub1 induced a rapid displacement of PRC2 activity and a loss of H3K27me3 deposition. This preferentially affected PRC2.2 variant with respect to PRC2.1, destabilizing canonical PRC1 activity. Finally, we found that variant PRC1 forms can sense H2AK119ub1 deposition, which contributes to their stabilization specifically at sites where this modification is highly enriched. Overall, our data place H2AK119ub1 deposition as a central hub that mounts PcG repressive machineries to preserve cell transcriptional identity.

| S-EPMC7033561 | biostudies-literature

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