Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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 sensitivity 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. Genetically engineered mouse melanoma studies indicate that loss of Mi-2β rescued the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq indicate that Mi-2β controlled the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β bound to EZH2 and promote K510 methylation of EZH2 and subsequently activate the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which targeted inhibition of Mi-2β ATPase activity and recovered ISG transcription. Consequently, Z36-MP5 efficiently induce a response to immunotherapy in otherwise resistant melanomas. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.

ORGANISM(S): Mus musculus

PROVIDER: GSE255782 | GEO | 2024/02/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Functional interactions between Mi-2β and AP1 complexes control response and recovery from barrier disruption

Project description:Keratinocytes respond to environmental signals by eliciting induction of genes that preserve skin’s integrity. Here we show that the transcriptional response to stress signaling is supported by short-lived epigenetic changes. Comparison of chromatin accessibility and transcriptional changes induced by barrier disruption or by loss of the nucleosome remodeler Mi-2β identified their striking convergence in mouse and human keratinocytes. Mi-2β directly repressed genes induced by barrier disruption by restricting AP1-enriched promoter-distal sites, occupied by Mi-2β and JUNB at steady state and by c-JUN after Mi-2β depletion or stress signaling. Barrier disruption led to a modest reduction in Mi-2β expression and a further selective reduction of Mi-2β localization at stress response genes possibly through competition with activated c-JUN. Consistent with a repressive role at stress response genes, genetic ablation of Mi-2β did not prevent re-establishment of barrier integrity but was required for return to homeostasis. Thus a competition between Mi-2β repressive and activating AP1 complexes may permit rapid transcriptional response to and resolution from stress signaling.

2019-12-03 | GSE139685 | GEO

Mi-2β knockout enhanced response of B16F10 cells to IFN-γ

Project description:Mi-2β-knockout and non-target control B16F10 cell lines were created using a clustered regular interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system. Total RNA was extracted from Mi-2β knockout and control B16F10 cells, which were treated with IFN-γ (10ng/mL) for 24 hours, for microarray assay. The experimental group cells were cultured in triplicate. The experiment was comprised of 6 Mouse Gene 2.0 ST arrays.

2023-05-23 | GSE151640 | GEO

Direct control of regulatory T cells by keratinocytes

Project description:Environmental challenges to epithelial cells trigger gene expression changes that elicit context-appropriate immune responses. Here we show that the chromatin remodeler Mi-2β controls epidermal homeostasis by holding genes involved in keratinocyte and immune-cell activation at an inactive state. Mi-2β depletion caused rapid deployment of both a pro-inflammatory and an immunosuppressive response in the skin. A key target of Mi-2β in keratinocytes was the pro-inflammatory cytokine Thymic Stromal Lymphopoietin (TSLP). Loss of TSLPR signaling specifically in regulatory T cells (Treg) prevented their activation and permitted rapid progression from a skin pro-inflammatory response to a lethal systemic condition. Thus, in addition to their well-characterized role in pro-inflammatory responses, keratinocytes also directly support immune-suppressive responses that are critical for re-establishing organismal homeostasis.

2017-01-09 | GSE90573 | GEO

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 |

AP-2β activates enhancers that define mammary hormone sensing cell identity [RNA-seq]

Project description:The Activating Protein 2β transcription factor (TFAP2B; AP-2β) is a marker for both lobular and molecular apocrine/HER2-E breast cancers, despite these tumours having very different prognoses. We show that simultaneous expression of both AP-2β and the estrogen receptor (ESR1, ER) marks well differentiated, low proliferation cells that are characteristic of luminal A lobular tumours, but loss of ER expression occurs when the tumour cells progress to molecular apocrine tumours. To discover potential explanations for this behaviour we performed chromatin immunoprecipitation sequencing (ChIP-seq) for AP-2β, AR, GATA3, FOXA1 and H3K27 acetylation in ER-negative MDA-MB-453 breast cancer cells. We find that all four transcription factors frequently bind to the same enhancers and that these enhancers are more likely to be active when AP-2β is present. Molecular apocrine genes are significantly more likely to have enhancers bound to all four transcription factors flanked by H3K27 acetylation. When AP-2β binds separately from the other factors, it binds close to the transcription start site, where it shows very high enrichment for H3K27 acetylation. AP-2 family proteins activate transcription by recruiting CITED proteins and p300/CBP. Since AR, FOXA1 and GATA3 are themselves able to recruit histone acetyl-transferases, we infer that AP-2β regulates the activity of those histone acetyl-transferases. We propose that this broad fundamental role in transcription explains the contradictory functions, both oncogenic and tumour suppressing, that have been assigned to AP-2 family members in previous studies on cancer.

2023-12-31 | GSE207472 | GEO

AP-2β activates enhancers that define mammary hormone sensing cell identity [ChIP-Seq]

2023-12-31 | GSE207230 | GEO

Expression profiling of mouse melanomas with or without UVB-induced neoantigens and after combination immunotherapy

Project description:Syngeneic grafts of the D4M.3A.3 (parental) mouse melanoma cell line (derived from a Tyr::CreER;BrafCA;Ptenlox/lox mouse) in C56BL/6 mice model poorly immunogenic, low neoantigen human melanomas. The D3UV2 (UV2) cell line was derived by serial UVB irradiation and single cell cloning. The addition of UVB-induced putative neoantigens sensitizes UV2 syngeneic melanoma grafts to immune checkpoint inhibitors and triggers epitope skewing to tumor-lineage self-antigens, a phenomenon that can be successfully mimicked in parental melanomas through treatment combinations such as anti-PD-1 with ablative fractional photothermolysis and imiquimod. Our mouse models were used to characterize gene expression changes between neoantigen rich and neoantigen poor melanomas, and with immunotherapy.

2021-02-16 | GSE159344 | GEO

Ezh2Y641F mutations co-operate with Stat3 to enhance MHC Class I antigen processing and alter the tumor immune response in melanoma

Project description:Enhancer of Zeste Homolog 2 (EZH2) is the catalytic component of the Polycomb Repressive Complex 2, a chromatin modifying complex, which mediates methylation of lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark. Genetic alterations in EZH2 in melanoma include amplifications and activating point mutations at tyrosine 641 (Y641) whose underlying oncogenic mechanisms remain largely unknown. Here, we found that expression of Ezh2Y641F causes upregulation of a subset of interferon-regulated genes in melanoma cells. Upregulation of these genes was not a direct effect of changes in H3K27me3, but via a non-canonical interaction between Ezh2 and Signal Transducer and Activator of Transcription 3 (Stat3). Ezh2 and Stat3 together function as transcriptional activators to mediate gene activation of numerous genes, including MHC-Ib antigen processing genes. Furthermore, expression of Stat3 is required to maintain an anti-tumor immune response in Ezh2Y641F melanomas and to prevent melanoma progression and recurrence.

2022-09-30 | GSE183819 | GEO

EZH2-mediated primary cilium deconstruction drives metastatic melanoma formation

Project description:Human melanomas frequently harbor amplifications of EZH2. However, the oncogenic contribution of this methyltransferase to melanoma formation has remained elusive. Taking advantage of murine melanoma models, we now show that EZH2 drives tumorigenesis from benign BrafV600E or NrasQ61K-expressing melanocytes. EZH2 oncogenicity results from silencing of genes relevant for the integrity of the primary cilium, a signaling organelle projecting from the surface of vertebrate cells. Consequently, gain of EZH2 function promotes loss of primary cilia in benign melanocytic lesions. In contrast, blockade of EZH2 activity evokes ciliogenesis and cilia-dependent growth inhibition in malignant melanoma. Finally, we demonstrate that loss of cilia enhances pro-tumorigenic WNT/β-catenin signaling and is itself sufficient to drive metastatic melanoma in benign cells. Thus, primary cilia deconstruction is a key process in EZH2-driven melanomagenesis.

2019-04-04 | GSE112677 | GEO

Clinical Proteomics of Metastatic Melanoma Reveals Profiles of Organ-Specificity and Treatment Resistance

Project description:Immunotherapy and targeted therapy dramatically changed the treatment of metastatic melanoma. Yet, many patients do not respond to these treatments and improve the understanding of response and resistance is an urgent need. Thus, we utilized mass spectrometry-based proteomic analysis of 185 metastatic melanoma samples. Metastases from different sites demonstrate differences in cellular processes such as immune, metabolism, translation and proliferation. Complementary epidemiology analysis uncovers prognosis variance between different metastases locations after treated with anti-PD1. Examination of lung melanoma metastases reveals clinical and molecular heterogeneity that mainly reflected in immune-related processes. Analysis of BRAF mutation status and prior treatments with MAPK inhibitors also indicate differences in immune and metabolic processes and suggest a molecular basis for the combination of immunotherapy and targeted therapy. These results shed new light into biology and therapeutic resistant mechanisms and the pathogenesis of metastatic melanoma.

2020-12-23 | PXD020618 | Pride

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