Dual inhibition of EZH2 and G9a suppresses multiple myeloma cell proliferation by regulating interferon signal and IRF4-MYC axis
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PROVIDER: PRJNA648764 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetic mechanisms including histone modifications play key roles in the pathogenesis of multiple myeloma (MM). We have previously shown that a histone H3 lysine 27 (H3K27) methyltransferase EZH2 and a H3K9 methyltransferase G9a are potential therapeutic targets in MM. Recent studies suggested that EZH2 and G9a cooperate to regulate gene expression. We thus aimed to evaluate the anti-tumor effect by dual targeting of EZH2 and G9a in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed myeloma cell proliferation through inducing cell cycle arrest and apoptosis in vitro. Dual inhibition of EZH2 and G9a also repressed xenograft formation by myeloma cells in vivo. Higher expression levels of EZH2 and EHMT2, which encodes G9a, are significantly associated with poorer prognosis in MM patients, respectively. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in myeloma cells. Notably, we found increased expression and reduced H3K27/H3K9 methylation levels of endogenous retrovirus (ERV) genes in myeloma cells with the dual inhibition, suggesting that activation of the ERV genes may cause the IFN response. These results suggest that dual targeting of EZH2 and G9a may be a novel therapeutic strategy in MM.
2021-01-27 | GSE155135 | GEO
Project description: Not available
| S-EPMC7803977 | biostudies-literature
Project description:Immunomodulatory agents (IMiDs) and the next-generation Cereblon (CRBN) E3 ligase modulators (CeLMoDs), targeting the Ikaros/Aiolos-IRF4-MYC axis, are effective therapies for multiple myeloma (MM) across all stages of disease. Resistance to treatment can be acquired following exposure, but a subset of patients have primary resistance, with both states necessitating the development of alternative treatment strategies. Enhancer of zeste homolog 2 (EZH2) has been shown to have increased expression at myeloma relapse and higher expression is associated with a shorter progression free survival from diagnosis. EZH2 inhibitors have been studied as a single agent in myeloma and in combination treatments to overcome drug resistant in other malignancies. In this study KMS11 and RPMI-8226 myeloma cell lines are used as models of primary IMID resistance, with persistent Interferon regulatory factor 4 (IRF4) expression after IMiDs/CeLMoDs exposure without loss of cell viability. The combination of Tazemetostat, an FDA-approved EZH2 inhibitor, with IMiDs/CeLMoDs significantly reduces IRF4 expression, induces apoptosis, and leads to synergistic cell death in these resistant cell lines. Further investigations reveal that the synergistic effect of EZH2 inhibition is specific to IMiDs/CeLMoDs, is CRBN-dependent and rescued by IRF4 over-expression. Mechanistically, Tazemetostat appears to reduce Ikaros binding to the IRF4 promoter, explaining how the combination with IMiDs/CeLMoDs which also have this effect can reach the threshold required to suppress IRF4 expression and ultimately inhibit MM cell growth in resistant cell lines. Our findings highlight a potential strategy for treating MM patients with IMiD resistance.
2026-03-19 | PXD057933 | Pride
Project description:Purpose: The goal of this study is to evaluate H3K27me3 histone marks in retinal ganglion cells in Ezh2 (Math5Cre, Ezh2-/-) and combined G9a-Ezh2 (Math5Cre; G9a+/-Ezh2-/-) knockout mutant mice at P1. Both Ezh2 and G9a are major epigenetic silencing machineries. Ezh2 mediates the trimethylation of lysine 27 on histone 3. Emerging evidences show an interdependence between Ezh2 and G9a to facilitate K27 trimethylation. Methods: P1 retinal ganglion cells were collected and chromatin immunoprecipitation was performed with EZ- CHIP kit from Millipore. Library preparation was done with Rubicon Genomics Thruplex DNAseq. Results: Here, we find a pool of common K27me3 target genes of Ezh2 and G9a in double knockout that leads to dysfunction in double mutant RGCs. Conclusion: This study provides the first Chip-seq analysis of K27me3 in murine RGCs. Our data supports that an interaction between Ezh2 and G9a is also evident in murine retinal ganglion cells. This work should be a framework for further study of retinal ganglion cells and retinal diseases.
2022-07-29 | GSE118011 | GEO
Project description:Epigenetic modifications modulate gene expression and, when deregulated, contribute to the development and progression of cancer. G9a (EHMT2) and EZH2 are two histone methyltransferases commonly upregulated in several cancer types, leading to the silencing of tumor suppressor genes. We performed high throughput sequencing of a breast cancer cell line (MDA-MB-231), an ovarian cancer cell line (CAOV3) and a melanoma cell line (D14) treated with a G9a inhibitor (UNC0642), EZH2 inhibitor (GSK126) and their combination.
2022-02-20 | GSE168763 | GEO
Project description:Epigenetic mark deposition during embryonic development contribute to postnatal homeostasis and tissue stability. Previously, we found out that Ezh2 contributes critically to the function and postnatal cell survival in bipolar cells but not in retinal ganglion cells in the retina. (Yan et al. Postnatal onset of retinal degeneration by loss of embryonic Ezh2 repression of Six1. Sci Report. doi:10.1038/srep33887; (Cheng L, Wong LJ, Yan N, Han RC et al. Ezh2 does not mediate retinal ganglion cell homeostasis or their susceptibility to injury. PLoS One 2018;13(2):e0191853.). In this study, we used RNA-seq to define up- and down regulated genes in both Ezh2 and G9a deficient (Math5Cre; Ezh2f/fG9af/+; dKO) retinal ganglion cells (RGC) to evaluate the hypothesis of Ezh2 and G9a interaction that has been discussed in other tissues but in the retina. ChIP-Seq was applied to evaluate H3K27me3 histone marks in retinal ganglion cells in wild type (WT), Ezh2 (Math5Cre; Ezh2-/-, sKO) and combined G9a-Ezh2 (Math5Cre; G9a+/-Ezh2-/-, dKO) knockout mutant mice at P1.
2022-07-26 | GSE136360 | GEO
Project description:The goal of this gene expression study was to identify genes whose expression depends on the transription factor IRF4 by knocking down it's expression using shRNA in two IRF4+ myeloma cell lines. Keywords: time series design Two myeloma lines were analyzed over a time course of IRF4-targeted shRNA induction. There are 3 time courses: two using KMS12 (biological replicates) and one with SKMM1. Within each time course there are technical replicates.
2010-05-26 | E-GEOD-9067 | biostudies-arrayexpress
Project description:Using RNA interference to identify IRF4 target genes. Keywords: time series design
2008-07-07 | GSE8958 | GEO
Project description:Dual G9A and EZH2 inhibition stimulates an anti-tumour immune response in ovarian high-grade serous carcinoma
| PRJEB44851 | ENA
Project description:The canonical function of EZH2 is methylation of H3K27, although important non-canonical roles have recently been described. EZH2 mutation or deregulated expression has been conclusively demonstrated in the pathogenesis and response to treatment of acute myeloid leukemia (AML), thus making it an attractive therapeutic target. In this study, we therefore investigated whether inhibition of EZH2 might also improve the response of non-APL AML cells to ATRA-based therapy. We focused on GSK-343, a pyridone-containing S-adenosyl-L-methionine (SAM) cofactor-competitive EZH2 inhibitor that is representative of its class, and HKMTI-1-005, a substrate-competitive dual inhibitor targeting EZH2 and the closely related G9A/GLP H3K9 methyltransferases. We found that treatment with HKMTI-1-005 phenocopied EZH2 knockdown and was more effective in inducing myeloid differentiation (both in the absence and presence of ATRA) than GSK-343, despite the efficacy of GSK-343 in terms of abolishing H3K27 trimethylation. Furthermore, transcriptomic analysis revealed that in contrast to treatment with GSK-343, HKMTI-1-005 upregulated the expression of myeloid differentiation pathway genes with and without ATRA, while downregulating genes associated with a hematopoietic stem cell phenotype. Expression data (by HuGene 1.0 ST Affymetrix arrays) from HL-60 AML cells treated for 3 days with EZH2 inhibitors (10µM GSK343 or 2.5µM HKMTI-1-005) with or without AtRA (0.1µM) as well as data from HL-60 cells stabelly transduced with EZH2 KD (shEZH2#1 and shEZH2#2) or control (Scr) lentiviruses, selected and expanded for ~20 days with or without treatment with 0.1µM AtRA for 3 days.
2023-03-10 | GSE222616 | GEO