Antihistamine Drug Ebastine inhibits cancer growth by targeting Polycomb Group Protein EZH2
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ABSTRACT:
PROVIDER: PRJNA643550 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR12129119.fastq.gz | Fastqsanger.gz | |||
| SRR12129119_1.fastq.gz | Fastqsanger.gz | |||
| SRR12129119_2.fastq.gz | Fastqsanger.gz | |||
| SRR12129120.fastq.gz | Fastqsanger.gz | |||
| SRR12129120_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Antihistamine Drug Ebastine inhibits cancer growth by targeting Polycomb Group Protein EZH2
2020-07-02 | GSE153652 | GEO
Project description:Enhancer of zester homolog 2 (EZH2), a histone lysine methyltransferase and the catalytic component of polycomb repressive complex 2, has been extensively investigated as a chromatin regulator and a transcriptional suppressor by methylating H3 at lysine 27 (H3K27). EZH2 is upregulated or mutated in most cancers, and its expression levels are negatively associated with clinical outcomes. However, the current developed small-molecule inhibitors targeting EZH2 enzymatic activities could not inhibit the growth and progression of solid tumors. Here, we discovered an antihistamine drug, ebastine, as a novel EZH2 inhibitor by targeting EZH2 transcription and subsequently downregulating EZH2 protein level and H3K27 trimethylation in multiple cancer cell lines at concentrations below 10 μmol/L. The inhibition of EZH2 by ebastine further impaired the progression, migration, and invasiveness of these cancer cells. Overexpression of Ezh2 wild-type and its mutant, H689A (lacking methyltransferase activity), rescued the neoplastic properties of these cancer cells after ebastine treatment, suggesting that EZH2 targeted by ebastine is independent of its enzymatic function. Next-generation RNA-sequencing analysis also revealed that C4-2 cells treated with 8 μmol/L ebastine showed a gene profiling pattern similar to EZH2-knockdown C4-2 cells, which was distinctively different from cells treated with GSK126, an EZH2 enzyme inhibitor. In addition, ebastine treatment effectively reduced tumor growth and progression, and enhanced progression-free survival in triple-negative breast cancer and drug-resistant castration-resistant prostate cancer patient-derived xenograft mice. Our data demonstrated that ebastine is a novel, safe, and potent anticancer agent for patients with advanced cancer by targeting the oncoprotein EZH2.
| S-EPMC7541747 | biostudies-literature
Project description:Polycomb group proteins are important epigenetic regulators for organ development, cell proliferation and differentiation, as well as initiation and progression of lethal diseases, including cancer. Upregulated Polycomb group proteins, including EZH2, promote proliferation, migration, invasion and metastasis of cancer cells, as well as self-renewal of cancer stem cells. The canonical function of EZH2, along with its essential binding partners EED and SUZ12, is to methylate histone H3K27 and repress its downstream targets. In this study, we discover that EZH2 regulates androgen receptor (AR) expression levels and AR signaling in prostate cancer. Targeting EZH2 with the newly identified EZH2 inhibitor, astemizole, could effectively inhibit the progression of castration-resistant prostate cancer.
2018-12-22 | GSE124268 | 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:Diffuse Intrinsic Pontine Glioma (DIPG) is a rare and highly aggressive pediatric tumor. The average survival time after diagnosis is less than one year. Currently, there are no effective treatments. Characteristic of DIPG is a mutation in histone H3 which leads to a substitution of Lysine 27 to Methionine (H3K27M) which deregulates Polycomb Repressive Complex 2 (PRC2), including enzymatic activity of EZH2. Previous studies have shown that inhibition of EZH2 by chemical agents decreases DIPG cell proliferation and inhibits tumor growth in vivo. My thesis project aims to confirm that EZH2 could be a therapeutic target using chemical EZH2 inhibitors, small interfering RNAs and a CRISPR/Cas9 approach in a series of DIPG tumor cell lines and to determine underlying molecular mechanisms of action.
2022-04-01 | PXD017525 | Pride
Project description:Acquisition of drug resistance remains a chief impediment to successful cancer therapy, and we previously described a transient drug-tolerant cancer cell population (DTPs) whose survival is in part dependent on the activities of the histone methyltransferases G9a/EHMT2 and EZH2, the latter being the catalytic component of the polycomb repressive complex 2 (PRC2). Here, we applied multiple proteomic techniques to better understand the role of these HMTs in the establishment of the DTP state. Proteome-wide comparisons of lysine methylation patterns revealed that DTPs have increased methylation on K116 of PRC member Jarid2, an event that helps stabilize and recruit PRC2 to chromatin. We also found that EZH2, in addition to methylating histone H3K27, also methylates G9a at K185, and that methylated G9a better recruits repressive complexes to chromatin; similar to complexes recruited by histone H3 methylated at K9. Finally, a detailed histone posttranslational modification (PTM) analysis shows that EZH2, either directly or through its ability to methylate G9a, alters H3K9 methylation in the specific context of H3 serine10 phosphorylation, and primarily in a cancer cell subpopulation that serves as DTP precursors. We also show that combinations of histone PTMs recruit a different set of complexes to chromatin, shedding light on the temporal mechanisms that contribute to drug tolerance.
2020-01-24 | MSV000084838 | MassIVE
Project description:SPINK1 overexpression defines the second largest subtype of prostate cancer (PCa), however molecular mechanisms underlying its upregulation remains poorly understood. Here, we identified the role of miR-338-5p and miR-421 in post-transcriptional regulation of SPINK1. We established that miR-338-5p/miR-421 mediates several cellular responses against SPINK1-positive cancer by targeting oncogenic long non-coding RNA (lncRNA) MALAT1, inducing cell-cycle arrest, inhibiting epithelial-to-mesenchymal transition (EMT), cancer-stemness and drug resistance. Moreover, ectopic expression of miR-338-5p/miR-421 abrogates SPINK1-mediated oncogenesis, tumor growth and distant metastases in murine model. Importantly, RNA-sequencing expression analysis revealed an inverse correlation between miRNAs and SPINK1 or MALAT1 in PCa patients’ specimens. Further, we demonstrate Polycomb group protein EZH2-mediated epigenetic silencing of miR-338-5p/miR-421 in SPINK1-positive subtype. Thus, restoring miR-338-5p/miR-421 expression using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis by targeting multiple oncogenic pathways and eliciting anti-cancer pleiotropic effects. Taken together, the present study unravels the molecular mechanism underlying SPINK1 overexpression and suggests miR-338-5p and miR-421 replacement therapy for the treatment of SPINK1-positive malignancies.
2018-12-30 | GSE108558 | GEO
Project description:Polycomb group (PcG) proteins form multiprotein complexes, called Polycomb repressive complexes (PRCs). PRC2 contains the PcG proteins EZH2, SUZ12, and EED and represses transcription through methylation of lysine (K) 27 of histone H3 (H3). Suz12 is essential for PRC2 activity and its inactivation results in early lethality of mouse embryos.
2011-08-12 | GSE31354 | GEO
Project description:We studied transcriptional changes by Affymetrix human microarrays in DLBCL cell lines as a result of treatment with GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and is responsible for repressing target gene expression through methylation of histone H3 on lysine 27 (H3K27). Over-expression of EZH2 is implicated in tumorigenesis and correlates with poor prognosis in multiple tumor types. Recent reports have identified somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The Y641 residue is the most frequently mutated residue, with 22% of GCB (Germinal Cell B-cell) DLBCL and FL harboring mutations at this site. These lymphomas exhibit increased H3K27 tri-methylation (H3K27me3) due to altered substrate preferences of the mutant enzymes. However, it is unknown whether direct inhibition of EZH2 methyltransferase activity alone will be effective in treating lymphomas carrying activating EZH2 mutations. Herein, we demonstrate that GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and dramatically inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma. 10 DLBCL cell lines (7 mutant and 3 wild type EZH2), that were differentially sensitive to GSK126 in proliferation assays, were treated for 72 hours, in duplicate (n=2), with either DMSO (vehicle) or 500nM of GSK126, a potent selective EZH2 inhibitor. EZH2 mutant cell lines are Pfeiffer, KARPAS-422, WSU-DLCL2, SU-DHL-10, SU-DHL-6, DB and SU-DHL-4. EZH2 wildtype cell lines are HT, OCI-LY-19 and Toledo.
2012-10-12 | E-GEOD-40971 | biostudies-arrayexpress
Project description:ChIP-seq was performed for Ring1b, Ezh2, Cbx2 and H3K27me3 in ESCs and Ring1b and H3K27me3 in NSCs. This was used to define Polycomb-bound regions and to assess their H3.3 enrichment and turnover using time-ChIP.
2016-06-20 | GSE78899 | GEO