Homo sapiens
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PROVIDER: PRJNA345622 | ENA |
REPOSITORIES: ENA
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Project description:EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions
| PRJNA345618 | ENA
Project description:EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions [mRNA expression]
| PRJNA345623 | ENA
Project description:Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite current progress in improving patient outcome, MM remains largely incurable. Disease clonal and interpatient heterogeneity has hampered identification of a common underlying mechanism for disease establishment and have slowed the development of novel targeted therapies. Epigenetic aberrations are now emerging as increasingly important in tumorigenesis, thus selective targeting of crucial epigenetic enzymes may provide new therapeutic potential in cancer including MM. Recently, we and others suggested the histone methyltransferase enhancer of zeste homolog 2 (EZH2), to be a potential therapeutic target in MM. Now we show that pharmacological inhibition of EZH2 suppresses the MM cell growth through downregulation of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1and c-MYC. We also show that downregulation of these genes is mediated via reactivated expression of microRNAs with tumor suppressor functions; primarily miR125a-3p and miR320c. Using chromatin immunoprecipitation (ChIP) we demonstrate that miR125a-3p and miR320c are targets of EZH2 and H3K27me3 in MM cell lines and primary MM cells. Our results further highlight the importance of polycomb-mediated silencing in MM to include microRNAs with tumor suppressor activity. This novel role further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.
2017-01-10 | GSE87715 | GEO
Project description:Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite current progress in improving patient outcome, MM remains largely incurable. Disease clonal and interpatient heterogeneity has hampered identification of a common underlying mechanism for disease establishment and have slowed the development of novel targeted therapies. Epigenetic aberrations are now emerging as increasingly important in tumorigenesis, thus selective targeting of crucial epigenetic enzymes may provide new therapeutic potential in cancer including MM. Recently, we and others suggested the histone methyltransferase enhancer of zeste homolog 2 (EZH2), to be a potential therapeutic target in MM. Now we show that pharmacological inhibition of EZH2 suppresses the MM cell growth through downregulation of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1and c-MYC. We also show that downregulation of these genes is mediated via reactivated expression of microRNAs with tumor suppressor functions; primarily miR125a-3p and miR320c. Using chromatin immunoprecipitation (ChIP) we demonstrate that miR125a-3p and miR320c are targets of EZH2 and H3K27me3 in MM cell lines and primary MM cells. Our results further highlight the importance of polycomb-mediated silencing in MM to include microRNAs with tumor suppressor activity. This novel role further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.
2017-01-10 | GSE87714 | GEO
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:MicroRNAs may act as oncogenes or tumour suppressor genes, which make these small molecules potential diagnostic/prognostic factors and targets for anticancer therapies. On account of this, we performed large-scale profiling of microRNA expression in canine mammary cancer.
2017-11-09 | GSE103093 | GEO
Project description:Epigenetic regulators are commonly mutated in cancer. Activating mutations and overexpression of the lysine histone methyltransferase EZH2 occur in lymphoma and other malignancies, while loss-of-function mutations are found in myeloid malignancies. We study this apparent contradiction, examining the importance of cellular context for Ezh2 loss during the evolution of a single malignancy, Acute Myeloid Leukemia (AML). Remarkably, we observe diametrically opposite functions for Ezh2 at early and late stages during the evolution of leukemias generated by different AML-associated fusion-oncogenes. During disease maintenance we demonstrate that Ezh2 functions as an oncogene that may be therapeutically targeted. In contrast, Ezh2 acts as a tumour suppressor during AML induction and loss-of-function EZH2 mutations occur early in AML patient samples and confer a poor prognosis. Integrated genomic analysis demonstrates that different expression programmes are de-repressed during AML induction and maintenance following Ezh2 loss. During disease induction, Ezh2 loss de-represses a subset of bivalent promoters that resolve towards gene activation, inducing a feto-oncogene programme including genes such as Plag1, whose overexpression phenocopies Ezh2 loss to accelerate AML induction in mouse models. Our data highlight the importance of cellular context and phase of disease evolution for Ezh2 function. Moreover, we further identify EZH2 as a potential target in AML, whilst providing reassurance of the safety of this therapeutic strategy.
2019-03-07 | GSE112724 | GEO
Project description:MicroRNAs have been demonstrated to be deregulated in multiple myeloma (MM). We have previously reported the downregulation of miR-214 in MM compared to normal plasma cells. In the present study, we have explored the functional role of miR-214 in myeloma pathogenesis. Ectopic expression of miR-214 reduced cell growth and induced apoptosis of myeloma cells. In order to identify the potential direct target genes of miR-214 which could be involved in the biological pathways regulated by this miRNA, gene expression profiling of H929 myeloma cell line transfected with precursor miR-214 was carried out. Functional analysis revealed significant enrichment for DNA replication, cell cycle phase and DNA binding. We show that miR-214 directly down-regulates the expression of PSMD10, which encodes the oncoprotein gankyrin, and ASF1B, a histone chaperone required for DNA replication, by binding to their 3'-UTR. In addition, gankyrin inhibition induced an increase of P53 mRNA levels and subsequent up-regulation in CDKN1A (p21Waf1/Cip1) and BAX transcripts, which are direct transcriptional targets of p53. In conclusion, we demonstrate that miR-214 function as a tumor suppressor in myeloma by a positive regulation of p53 and inhibition of DNA replication. H929 cell line was transfected with Pre-miR™ miRNA precursors pre-miR-214 or pre-miR™ miRNA negative, non-targeting control#1 (Ambion) at 50 nM concentration, using the nucleofector II system with C-16 program (Amaxa). The experiments were performed in triplicates.
2012-12-28 | E-GEOD-35948 | biostudies-arrayexpress
Project description: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. Tiffen JC, Gunatilake D, Gallagher SJ, Gowrishankar K, Heinemann A, Cullinane C, et al. Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes. Oncotarget 2015;12:12
2019-11-15 | GSE140394 | GEO
Project description:in this study we define an epigenomic profile of PRC2 (H3K27me3 and bivalent) tragets in four newly diagnosed MM patients. Using Oncomine database we demonstarte that PRC2 targets are underexpressed with advanced ISS stages and correlated to poor outcome. Pharmacological inhibition of UNC1999 showed anti-myeloma potential in vitro by activating the expression genes related to apoptosis and cell differenatiation. In this array the differences between the gene expression profiles of samll molecule inhibitor (UNC1999) of EZH2 and the control (UNC2400) have been tested. So multiple myeloma cell line INA-6 was treated with 2μM of UNC1999 and UNC2400. This design contains three biological replicates.
2015-12-31 | E-GEOD-69251 | biostudies-arrayexpress