Integration of epigenomic and transcriptomic profiling uncovers EZH2 target genes linked to cysteine metabolism in hepatocellular carcinoma
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ABSTRACT:
PROVIDER: PRJNA997288 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25385846_1.fastq.gz | Fastqsanger.gz | |||
| SRR25385846_2.fastq.gz | Fastqsanger.gz | |||
| SRR25385847_1.fastq.gz | Fastqsanger.gz | |||
| SRR25385847_2.fastq.gz | Fastqsanger.gz | |||
| SRR25385848_1.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2024-10-24 | GSE237952 | GEO
Project description:Epigenetic dysregulation is closely associated with the pathogenesis of hepatocellular carcinoma (HCC). Enhancer of zeste homolog 2 (EZH2) is a key protein involved in the exacerbation of various cancers, including HCC. Despite several clinical trials of epigenetic therapies targeting EZH2, the mechanisms underlying EZH2-mediated gene suppression in HCC are not fully understood. In this study, we investigated EZH2-mediated transcriptional programs under EZH2-selective inhibition through an integrative analysis of epigenomic (ATAC-seq) and transcriptomic (RNA-seq) approaches. To determine the impact of EZH2 dysfunction, we measured the levels of H3K27me3 and EZH2 expression using flow cytometry and reverse transcription quantitative real-time PCR (RT-qPCR), respectively. Notably, we found that higher expression of EZH2 was significantly correlated with poorer survival among HCC patients by reanalyzing transcriptomes in the cancer genome atlas (TCGA). Inhibition of EZH2 with Tazemetostat (EPZ-6438), a selective inhibitor of EZH2, showed that EZH2 regulates genes involved in lipid homeostasis, and cysteine-methionine metabolism. Among the 13 EZH2 target genes identified by transcriptomic and epigenomic profiling, we selected BHMT and CDO1, which were significantly associated with poor survival in HCC patients. When HCC cells were treated with Tazemetostat, the expression levels of the BHMT and CDO1 genes increased, while the expression levels of ferroptosis marker genes, such as FSP1, NFS1, and SLC7A11, decreased. This suggests that inhibiting EZH2 may have potential therapeutic benefits in HCC by regulating the expression of genes involved in important biological processes. Our study suggests that EZH2 epigenetically regulates ferroptosis by controlling cysteine metabolism in HCC.
2024-10-25 | GSE237948 | GEO
Project description:Epigenetic dysregulation is closely associated with the pathogenesis of hepatocellular carcinoma (HCC). Enhancer of zeste homolog 2 (EZH2) is a key protein involved in the exacerbation of various cancers, including HCC. Despite several clinical trials of epigenetic therapies targeting EZH2, the mechanisms underlying EZH2-mediated gene suppression in HCC are not fully understood. In this study, we investigated EZH2-mediated transcriptional programs under EZH2-selective inhibition through an integrative analysis of epigenomic (ATAC-seq) and transcriptomic (RNA-seq) approaches. To determine the impact of EZH2 dysfunction, we measured the levels of H3K27me3 and EZH2 expression using flow cytometry and reverse transcription quantitative real-time PCR (RT-qPCR), respectively. Notably, we found that higher expression of EZH2 was significantly correlated with poorer survival among HCC patients by reanalyzing transcriptomes in the cancer genome atlas (TCGA). Inhibition of EZH2 with Tazemetostat (EPZ-6438), a selective inhibitor of EZH2, showed that EZH2 regulates genes involved in lipid homeostasis, and cysteine-methionine metabolism. Among the 13 EZH2 target genes identified by transcriptomic and epigenomic profiling, we selected BHMT and CDO1, which were significantly associated with poor survival in HCC patients. When HCC cells were treated with Tazemetostat, the expression levels of the BHMT and CDO1 genes increased, while the expression levels of ferroptosis marker genes, such as FSP1, NFS1, and SLC7A11, decreased. This suggests that inhibiting EZH2 may have potential therapeutic benefits in HCC by regulating the expression of genes involved in important biological processes. Our study suggests that EZH2 epigenetically regulates ferroptosis by controlling cysteine metabolism in HCC.
2024-10-25 | GSE268195 | GEO
Project description:Epigenetic dysregulation is closely associated with the pathogenesis of hepatocellular carcinoma (HCC). Enhancer of zeste homolog 2 (EZH2) is a key protein involved in the exacerbation of various cancers, including HCC. Despite several clinical trials of epigenetic therapies targeting EZH2, the mechanisms underlying EZH2-mediated gene suppression in HCC are not fully understood. In this study, we investigated EZH2-mediated transcriptional programs under EZH2-selective inhibition through an integrative analysis of epigenomic (ATAC-seq) and transcriptomic (RNA-seq) approaches. To determine the impact of EZH2 dysfunction, we measured the levels of H3K27me3 and EZH2 expression using flow cytometry and reverse transcription quantitative real-time PCR (RT-qPCR), respectively. Notably, we found that higher expression of EZH2 was significantly correlated with poorer survival among HCC patients by reanalyzing transcriptomes in the cancer genome atlas (TCGA). Inhibition of EZH2 with Tazemetostat (EPZ-6438), a selective inhibitor of EZH2, showed that EZH2 regulates genes involved in lipid homeostasis, and cysteine-methionine metabolism. Among the 13 EZH2 target genes identified by transcriptomic and epigenomic profiling, we selected BHMT and CDO1, which were significantly associated with poor survival in HCC patients. When HCC cells were treated with Tazemetostat, the expression levels of the BHMT and CDO1 genes increased, while the expression levels of ferroptosis marker genes, such as FSP1, NFS1, and SLC7A11, decreased. This suggests that inhibiting EZH2 may have potential therapeutic benefits in HCC by regulating the expression of genes involved in important biological processes. Our study suggests that EZH2 epigenetically regulates ferroptosis by controlling cysteine metabolism in HCC.
2024-10-25 | GSE237951 | 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:Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) for transcriptional repression. EZH2 have been implicated in numerous hematological malignancies, including MM. However, noncanonical functions of EZH2 in MM tumorigenesis are not well understood. Here, we uncovered a noncanonical function of EZH2 in MM malignancy. In addition to the PRC2-mediated and H3K27me3-dependent canonical function, EZH2 interacts with cMyc and co-localizes with gene activation markers, promoting MM tumorigenesis in a PRC2- and H3K27me3-independent manner. Both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes can be effectively depleted in MM cells by MS177, an EZH2 degrader we reported previously, leading to profound activation of EZH2-PRC2-associated genes and suppression of EZH2-cMyc oncogenic nodes. The MS177-induced degradation of both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes also reactivated immune response genes in MM cells. Phenotypically, targeting of EZH2’s both canonical and noncanonical functions by MS177 effectively suppressed the proliferation of MM cells both in vitro and in vivo. Collectively, this study uncovers a new noncanonical function of EZH2 in MM tumorigenesis and provides a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.
2023-01-25 | GSE214668 | GEO
Project description:Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) for transcriptional repression. EZH2 have been implicated in numerous hematological malignancies, including MM. However, noncanonical functions of EZH2 in MM tumorigenesis are not well understood. Here, we uncovered a noncanonical function of EZH2 in MM malignancy. In addition to the PRC2-mediated and H3K27me3-dependent canonical function, EZH2 interacts with cMyc and co-localizes with gene activation markers, promoting MM tumorigenesis in a PRC2- and H3K27me3-independent manner. Both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes can be effectively depleted in MM cells by MS177, an EZH2 degrader we reported previously, leading to profound activation of EZH2-PRC2-associated genes and suppression of EZH2-cMyc oncogenic nodes. The MS177-induced degradation of both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes also reactivated immune response genes in MM cells. Phenotypically, targeting of EZH2’s both canonical and noncanonical functions by MS177 effectively suppressed the proliferation of MM cells both in vitro and in vivo. Collectively, this study uncovers a new noncanonical function of EZH2 in MM tumorigenesis and provides a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.
2023-01-25 | GSE214667 | GEO
Project description:The responses of macrophages to lipopolysaccharide (LPS) might determine the direction of clinical manifestations of sepsis, which is the immune response against severe infection. Meanwhile, the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, might interfere with LPS response. With a single LPS stimulation, Ezh2 null(Ezh2flox/flox; LysM-Crecre/−) macrophages demonstrated lower supernatant TNF-α than Ezh2 control (Ezh2fl/fl; LysM-Cre−/−), perhaps due to an upregulation of Socs3, which is a suppressor of cytokine signaling 3, due to the loss of the Ezh2 gene. In LPS tolerance, Ezh2 null macrophages indicated higher supernatant TNF-α and IL-6 than the control, supporting an impact of the loss of the Ezh2 inhibitory gene. In parallel, Ezh2 null mice demonstrated lower serum TNF-α and IL-6 than the control mice after an LPS injection, indicating a less severe LPS-induced hyper-inflammation in Ezh2 null mice. In conclusion, an absence of Ezh2 in macrophages resulted in less severe LPS-induced inflammation, as indicated by low serum cytokines, with less severe LPS tolerance, as demonstrated by higher cytokine production, partly through the upregulated Socs3.
2023-07-20 | PXD041265 | Pride
Project description:First experiment: Cells were cultured in sulfur amino acid-free DMEM supplemented with 0.1 mM methionine + 0.1 mM cysteine (complete) or supplemented only with 0.1 mM methionine (cysteine-free). Cells were cultured in either medium for 42 h (Long + Cys; Long -Cys) or in cysteine-free medium for 36 h followed by 6 h in complete medium (Short +Cys) Second experiment: C3A/HepG2 cells were cultured in sulfur amino acid-free DMEM supplemented with 0.1 mM Met and 0.1 mM Cys (complete) or supplemented only with 0.1 mM Met (cysteine-devoid). Cells were cultured in complete medium for 42 h (Long +Cys) or in complete medium for 36 h followed by cysteine-devoid medium for 6 h (Short -Cys). Keywords: amino acid deprivation
2007-12-13 | GSE9517 | GEO
Project description:First experiment: Cells were cultured in sulfur amino acid-free DMEM supplemented with 0.1 mM methionine + 0.1 mM cysteine (complete) or supplemented only with 0.1 mM methionine (cysteine-free). Cells were cultured in either medium for 42 h (Long + Cys; Long -Cys) or in cysteine-free medium for 36 h followed by 6 h in complete medium (Short +Cys); Second experiment: C3A/HepG2 cells were cultured in sulfur amino acid-free DMEM supplemented with 0.1 mM Met and 0.1 mM Cys (complete) or supplemented only with 0.1 mM Met (cysteine-devoid). Cells were cultured in complete medium for 42 h (Long +Cys) or in complete medium for 36 h followed by cysteine-devoid medium for 6 h (Short -Cys). Experiment Overall Design: First experiment: Three plates of cells were cultured under each condition. Cells were cultured in sulfur amino acid-free DMEM supplemented with 0.1 mM methionine + 0.1 mM cysteine (complete) or supplemented only with 0.1 mM methionine (cysteine-free). Cells were cultured in either medium for 42 h (Long + Cys; Long -Cys) or in cysteine-free medium for 36 h followed by 6 h in complete medium (Short +Cys). Experiment Overall Design: Second experiment: C3A/HepG2 cells were cultured in sulfur amino acid-free DMEM supplemented with 0.1 mM Met and 0.1 mM Cys (complete) or supplemented only with 0.1 mM Met (cysteine-devoid). Cells were cultured in complete medium for 42 h (Long +Cys) or in complete medium for 36 h followed by cysteine-devoid medium for 6 h (Short -Cys).
2008-06-16 | E-GEOD-9517 | biostudies-arrayexpress