Browse
Submit Data
Databases
API
Help

Dataset Information

4 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes.

ABSTRACT: The epigenetic modifier EZH2 is part of the polycomb repressive complex that suppresses gene expression via histone methylation. Activating mutations in EZH2 are found in a subset of melanoma that contributes to disease progression by inactivating tumor suppressor genes. In this study we have targeted EZH2 with a specific inhibitor (GSK126) or depleted EZH2 protein by stable shRNA knockdown. We show that inhibition of EZH2 has potent effects on the growth of both wild-type and EZH2 mutant human melanoma in vitro particularly in cell lines harboring the EZH2Y646 activating mutation. This was associated with cell cycle arrest, reduced proliferative capacity in both 2D and 3D culture systems, and induction of apoptosis. The latter was caspase independent and mediated by the release of apoptosis inducing factor (AIFM1) from mitochondria. Gene expression arrays showed that several well characterized tumor suppressor genes were reactivated by EZH2 inhibition. This included activating transcription factor 3 (ATF3) that was validated as an EZH2 target gene by ChIP-qPCR. These results emphasize a critical role for EZH2 in the proliferation and viability of melanoma and highlight the potential for targeted therapy against EZH2 in treatment of patients with melanoma.

SUBMITTER: Tiffen JC

PROVIDER: S-EPMC4694971 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

EZH2 Inhibition as a Therapeutic Strategy for Lymphoma with EZH2 Activating Mutations

Project description:This SuperSeries is composed of the following subset Series: GSE40970: ChIP-seq analysis of H3K27me3 histone modification in EZH2 mutant and wild type DLBCL cell lines GSE40971: Gene expression profiling of EZH2 mutant and wild type DLBCL cell lines treated with EZH2 inhibitor GSE41239: Gene expression profiling of two DLBCL cell lines upon shRNA mediated knockdown of EZH2 Refer to individual Series

2012-10-12 | E-GEOD-40972 | biostudies-arrayexpress

Merkel Cell Carcinoma Sensitivity to EZH2 Inhibition Is Mediated by SIX1 Derepression.

Project description:Polycomb repressive complex 2 has a critical role in the maintenance of bivalent promoters and is often perturbed in cancer, including neuroendocrine tumors. In this study, we investigated the susceptibility of Merkel cell carcinoma (MCC), a neuroendocrine carcinoma of the skin, to inhibitors of the Polycomb repressive complex 2 catalytic subunit EZH2. We show that a subset of MCC cell lines is sensitive to EZH2 inhibitor-induced cell viability loss. We find that inhibitor treatment of susceptible cells derepresses the Polycomb repressive complex 2 target SIX1, a transcription factor in the PAX-SIX-EYA-DACH network normally involved in inner ear hair cell development, and that PAX-SIX-EYA-DACH network transcription factors are critical contributors to EZH2 inhibitor-induced MCC cell viability loss. Furthermore, we show the EZH2 inhibitor tazemetostat slows the growth of MCC xenografts and derepresses SIX1 and its downstream inner ear transcriptional target MYO6 in vivo. We propose that EZH2 inhibition in MCC leads to SIX1 derepression with dysregulation of hearing-related transcriptional programs and growth inhibition. This study provides evidence that MCC tumors may be specifically susceptible to EZH2 inhibitors, while giving mechanistic insight into the transcriptional programs these inhibitors perturb in MCC, and potentially in other neuroendocrine cancers.

| S-EPMC9492898 | biostudies-literature

EZH2 Inhibition as a Therapeutic Strategy for Lymphoma with EZH2 Activating Mutations

Project description:This SuperSeries is composed of the SubSeries listed below.

2012-10-12 | GSE40972 | GEO

Inhibition of EZH2 Causes Retrotransposon Derepression and Immune Activation in Porcine Lung Alveolar Macrophages.

Project description:Alveolar macrophages (AMs) form the first defense line against various respiratory pathogens, and their immune response has a profound impact on the outcome of respiratory infection. Enhancer of zeste homolog 2 (EZH2), which catalyzes the trimethylation of H3K27 for epigenetic repression, has gained increasing attention for its immune regulation function, yet its exact function in AMs remains largely obscure. Using porcine 3D4/21 AM cells as a model, we characterized the transcriptomic and epigenomic alterations after the inhibition of EZH2. We found that the inhibition of EZH2 causes transcriptional activation of numerous immune genes and inhibits the subsequent infection by influenza A virus. Interestingly, specific families of transposable elements, particularly endogenous retrovirus elements (ERVs) and LINEs which belong to retrotransposons, also become derepressed. While some of the derepressed ERV families are pig-specific, a few ancestral families are known to be under EZH2-mediated repression in humans. Given that derepression of ERVs can promote innate immune activation through "viral mimicry", we speculate that ERVs may also contribute to the coinciding immune activation in AMs after the inhibition of EZH2. Overall, this study improves the understanding of the EZH2-related immune regulation in AMs and provides novel insights into the epigenetic regulation of retrotransposons in pigs.

| S-EPMC9917017 | biostudies-literature

Selective inhibition of EZH2 by ZLD1039 blocks H3K27 methylation and leads to potent anti-tumor activity in breast cancer.

Project description:Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver due to its prevalent overexpression and aberrant repression of tumor suppressor genes in diverse cancers. Therefore, blocking EZH2 enzyme activity may present a valid therapeutic strategy for the treatment of cancers with EZH2 overexpression including breast cancers. Here, we described ZLD1039 a potent, highly selective, and orally bioavailable small molecule inhibitor of EZH2, which inhibited breast tumor growth and metastasis. ZLD1039 considerably inhibited EZH2 methyltransferase activity with nanomolar potency, decreased global histone-3 lysine-27 (H3K27) methylation, and reactivated silenced tumor suppressors connected to increased survival of patients with breast cancer. Comparable to conditional silencing of EZH2, its inhibition by ZLD1039 decreased cell proliferation, cell cycle arrest, and induced apoptosis. Comparably, treatment of xenograft-bearing mice with ZLD1039 led to tumor growth regression and metastasis inhibition. These data confirmed the dependency of breast cancer progression on EZH2 activity and the usefulness of ZLD1039 as a promising treatment for breast cancer.

| S-EPMC4751454 | biostudies-literature

Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation.

Project description:Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2β rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2β controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which reduces Mi-2β ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.

| S-EPMC10924921 | biostudies-literature

Targeting epigenetics in sarcomas through EZH2 inhibition.

Project description:Soft-tissue sarcomas represent a heterogeneous group of diseases with distinct genetic and clinical features accounting for up to 1% of cancer in adults and 15% of cancer in children. Epithelioid sarcoma is an extremely rare and aggressive tumor affecting young adults that is characterized by loss of INI1 expression. INI1 (SMARCB1, SNF5, BAF47) is a subunit of the SWI/SNF chromatin remodeling complex that opposes the enzymatic function of EZH2. When INI1 loses its regulatory function, EZH2 activity is de-regulated, allowing EZH2 to play a driving, oncogenic role. Tazemetostat, a specific EZH2 inhibitor, has just been approved for patients with advanced epithelioid sarcoma and represents a new therapeutic option in this devastating disease.

| S-EPMC7140314 | biostudies-literature

Inhibition of the epigenetic suppressor EZH2 primes osteogenic differentiation mediated by BMP2.

Project description:Bone-stimulatory therapeutics include bone morphogenetic proteins (e.g. BMP2), parathyroid hormone, and antibody-based suppression of WNT antagonists. Inhibition of the epigenetic enzyme enhancer of zeste homolog 2 (EZH2) is both bone anabolic and osteoprotective. EZH2 inhibition stimulates key components of bone-stimulatory signaling pathways, including the BMP2 signaling cascade. Because of high costs and adverse effects associated with BMP2 use, here we investigated whether BMP2 dosing can be reduced by co-treatment with EZH2 inhibitors. Co-administration of BMP2 with the EZH2 inhibitor GSK126 enhanced differentiation of murine (MC3T3) osteoblasts, reflected by increased alkaline phosphatase activity, Alizarin Red staining, and expression of bone-related marker genes (e.g. Bglap and Phospho1). Strikingly, co-treatment with BMP2 (10 ng/ml) and GSK126 (5 μm) was synergistic and was as effective as 50 ng/ml BMP2 at inducing MC3T3 osteoblastogenesis. Similarly, the BMP2-GSK126 co-treatment stimulated osteogenic differentiation of human bone marrow-derived mesenchymal stem/stromal cells, reflected by induction of key osteogenic markers (e.g. Osterix/SP7 and IBSP). A combination of BMP2 (300 ng local) and GSK126 (5 μg local and 5 days of 50 mg/kg systemic) yielded more consistent bone healing than single treatments with either compound in a mouse calvarial critical-sized defect model according to results from μCT, histomorphometry, and surgical grading of qualitative X-rays. We conclude that EZH2 inhibition facilitates BMP2-mediated induction of osteogenic differentiation of progenitor cells and maturation of committed osteoblasts. We propose that epigenetic priming, coupled with bone anabolic agents, enhances osteogenesis and could be leveraged in therapeutic strategies to improve bone mass.

| S-EPMC7278362 | biostudies-literature

Targeting glioma stem cells through combined BMI1 and EZH2 inhibition.

Project description:Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.

| S-EPMC5679732 | biostudies-literature

Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation

Project description:For identification of Mi-2β-interacting proteins, B16F10 cells (1 × 108) were collected and washed three times with PBS and lysed in lysis buffer on ice for 30 min. Cell lysates were collected and then isolated over night by anti-Mi-2β magnetic agarose beads. The anti-Mi-2β magnetic agarose beads were collected and washed three times with PBS. The prepared protein samples were incubated with sample buffer for 15 min at 100 °C, and then separated by SDS-PAGE (10%). The gel was immersed in staining solution (0.3% Coomassie blue, 45% methanol, 10% glacial acetic acid and 45% dH2O) on shaker for 30 min, followed by incubation in destaining solution (20% methanol, 10% glacial acetic acid, and 70% dH2O) on the shaker overnight. The bands were excised and sent to Biological Mass Spectrometry Facility of Shanghai Applied Protein Technology Co., Ltd for protein identification.

2024-02-18 | PXD049467 |

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data