Genome-wide maps of H3K27me3 and H3K27ac in cells treated with HDAC inhibition, EZH2 inhibition, or combined HDAC/EZH2 inhibition
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE150336 | GEO | 2020/05/12
REPOSITORIES: GEO
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Project description:Genome-wide maps of H3K27me3 and H3K27ac in cells treated with HDAC inhibition, EZH2 inhibition, or combined HDAC/EZH2 inhibition
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Project description:Expression data in PC3 prostate cancer cells treated with DMSO, HDAC inhibitor, EZH2 inhibitor, or combined HDAC and EZH2 inhibitors.
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Project description:Xenopus tropicalis tadpoles have the capability to scarlessly regenerate appendages including the limb and tail. Following injury, complex genetic processes must be activated and inactivated with high spatial and temporal resolution to result in a properly patterned appendage. Functional studies have established that histone modifying enzymes that act to close chromatin are required for regeneration, but the genomic regions sensitive to these activities are not established. Here we show that early inhibition of HDAC or Ezh2 activity results in incomplete regeneration. To identify the impact that each of these perturbations has on chromatin accessibility, we applied an assay for transposase accessible chromatin (ATAC-seq) to HDAC or Ezh2 inhibited regenerating tadpoles. We find that neither perturbation results in a global increase in chromatin accessibility, but that both inhibitors have targeted effects on chromatin accessibility and gene expression. Upon HDAC inhibition, promoter regions and regulatory regions neighboring genes associated with neuronal regeneration are precociously accessible, whereas following EZH2 inhibition we find gene bodies and regulatory regions associated with regulation of the immune response and apoptosis are preferentially accessible. Together this suggests distinct roles for EZH2 activity and HDAC activity in appendage regeneration.
2022-05-01 | GSE175662 | GEO
Project description:Transcriptional profiles were examined in PC3 prostate cancer cells treated with vehicle (DMSO), vorinostat (VOR, HDACi), GSK126 (GSK126, EZH2i) or all 3 agents (COMBO) at 72 hours, prior to the commencement of cell death, to investigate the molecular mechamism by which these drugs and their combinations are functioning.
2020-05-05 | GSE149784 | GEO
Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
2018-07-03 | PXD010073 | Pride
Project description:Gene list with increasing of expression in 2-fold or more after EZH2 knockdown in PC3 cells
2008-04-24 | E-MEXP-1581 | biostudies-arrayexpress
Project description:Background: Ewing sarcoma (EwS) are characterized by oncogenic chimeric EWS-ETS proteins. EZH2 is upregulated via predominant EWS-FLI1 in EwS. RNAi of EZH2 revealed an EZH2-maintained, undifferentiated, stemness phenotype. Herein, microarray analysis demonstrated that treatment with HDAC inhibitors (HDACi) entinostat or TSA resulted in the induction of a similar pattern of differentiation genes as observed after EZH2 RNAi. This indicates that EZH2-containing PRC2 complexes may serve as a building block of class I HDAC activity in EwS. Methods: The role of class I HDACs was determined using different inhibitors including TSA, romidepsin (FK228), entinostat (MS-275) and PCI-34051 as well as CRISPR/Cas9 class I HDAC knock outs and HDAC RNAi. To analyze resulting changes microarray and gene set enrichment analysis (GSEA), qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used. Results: Class I HDACs are constitutively expressed in EwS. They seem regulated via EWS-FLI1. Interestingly, patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knock out of individual HDACs such as HDAC1 and HDAC2 inhibited growth, invasiveness, and blocked local tumor growth in xenograft mice. Microarray and GSEA analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with first line chemotherapeutics including doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2. Conclusion: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi are interesting new treatment opportunities for this malignant disease.
2021-10-20 | GSE162786 | GEO
Project description:Background: Ewing sarcoma (EwS) are characterized by oncogenic chimeric EWS-ETS proteins. EZH2 is upregulated via predominant EWS-FLI1 in EwS. RNAi of EZH2 revealed an EZH2-maintained, undifferentiated, stemness phenotype. Herein, microarray analysis demonstrated that treatment with HDAC inhibitors (HDACi) entinostat or TSA resulted in the induction of a similar pattern of differentiation genes as observed after EZH2 RNAi. This indicates that EZH2-containing PRC2 complexes may serve as a building block of class I HDAC activity in EwS. Methods: The role of class I HDACs was determined using different inhibitors including TSA, romidepsin (FK228), entinostat (MS-275) and PCI-34051 as well as CRISPR/Cas9 class I HDAC knock outs and HDAC RNAi. To analyze resulting changes microarray and gene set enrichment analysis (GSEA), qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used. Results: Class I HDACs are constitutively expressed in EwS. They seem regulated via EWS-FLI1. Interestingly, patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knock out of individual HDACs such as HDAC1 and HDAC2 inhibited growth, invasiveness, and blocked local tumor growth in xenograft mice. Microarray and GSEA analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with first line chemotherapeutics including doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2. Conclusion: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi are interesting new treatment opportunities for this malignant disease.
2021-10-20 | GSE162785 | GEO
Project description:Background: Ewing sarcoma (EwS) are characterized by oncogenic chimeric EWS-ETS proteins. EZH2 is upregulated via predominant EWS-FLI1 in EwS. RNAi of EZH2 revealed an EZH2-maintained, undifferentiated, stemness phenotype. Herein, microarray analysis demonstrated that treatment with HDAC inhibitors (HDACi) entinostat or TSA resulted in the induction of a similar pattern of differentiation genes as observed after EZH2 RNAi. This indicates that EZH2-containing PRC2 complexes may serve as a building block of class I HDAC activity in EwS. Methods: The role of class I HDACs was determined using different inhibitors including TSA, romidepsin (FK228), entinostat (MS-275) and PCI-34051 as well as CRISPR/Cas9 class I HDAC knock outs and HDAC RNAi. To analyze resulting changes microarray and gene set enrichment analysis (GSEA), qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used. Results: Class I HDACs are constitutively expressed in EwS. They seem regulated via EWS-FLI1. Interestingly, patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knock out of individual HDACs such as HDAC1 and HDAC2 inhibited growth, invasiveness, and blocked local tumor growth in xenograft mice. Microarray and GSEA analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with first line chemotherapeutics including doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2. Conclusion: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi are interesting new treatment opportunities for this malignant disease.
2021-10-20 | GSE162788 | GEO
Project description:Background: Upregulation of H3K27me3 induced by EZH2 overexpression or somatic heterozygous mutations were implicated in lymphomagenesis. It has been demonstrated that several EZH2-target agents have notable therapeutic effects in EZH2-mutant B-cell lymphoma patients. Here we present a novel highly selective EZH2 inhibitor SHR2554 and possible combination strategy in diffuse large B cell lymphoma (DLBCL); Methods: Cell proliferation, cycle and apoptosis were analyzed by Cell Titer-Glo Luminescent Cell Viability Assay and flow cytometry. Western Blot was used to detect the regulatory protease in related signaling pathways and RNA-seq was conducted to assess transcriptome changes. Finally, CDX and PDX models were used to evaluate the synergistic anti-tumor effects of the combination in vivo; Results: The novel EZH2 inhibitor SHR2554 could inhibited proliferation, induced G1 phase arrest in EZH2-mutant DLBCL cell lines. The combination of EZH2 inhibitor SHR2554 with histone deacetylase (HDAC) inhibitor chidamide (hereafter referred as HBI8000) exerted synergistic anti-proliferative activity in vitro and in vivo. Gene expression profile analysis revealed dramatic inhibition of DNA replication process in combined treatment; Conclusions: SHR2554, a potent highly selective small molecule inhibitor of EZH2, inhibited EZH2-mutant DLBCL more significantly in vitro and in vivo. The combination of HDAC inhibitor HBI8000 with EZH2 inhibitor SHR2554 exhibited dramatically anti-tumor activity in both mutant and wild-type DLBCL, which may become potential therapeutic modality for the treatment of DLBCL patients.
2021-07-12 | GSE179792 | GEO