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Loss of the Histone Methyltransferase EZH2 induces Resistance to Multiple Drugs in Acute Myeloid Leukemia

ABSTRACT: Loss of the Histone Methyltransferase EZH2 induces Resistance to Multiple Drugs in Acute Myeloid Leukemia

PROVIDER: PRJNA262102 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR1586170.fastq.gz	Fastqsanger.gz
	SRR1586180.fastq.gz	Fastqsanger.gz
	SRR1586190.fastq.gz	Fastqsanger.gz
	SRR1586161.fastq.gz	Fastqsanger.gz
	SRR1586171.fastq.gz	Fastqsanger.gz

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Loss of the Histone Methyltransferase EZH2 induces Resistance to Multiple Drugs in Acute Myeloid Leukemia

Project description:Poor outcome of AML patients is closely related with therapy failure or relapse after initial response. The underlying mechanisms remain largely unknown. In this study we discovered the histone methyltransferase EZH2 as a novel marker for response to chemotherapy and patients` survival. Protein levels of EZH2 and subsequently H3K27 trimethylation (H3K27me3) are reduced in chemoresistant AML cells. To analyze which genomic regions were affected by the loss of EZH2 and reduced H3K27me3 mark we performed Chromatin Immunoprecipitation followed by high-throughput DNA sequencing (ChIP-Seq). ChIP-Seq for the H3K27me3 repressive mark revealed genome-wide differences between sensitive (MV4-11) and resistant (MV4-11R) cells. Overall, 4699 genomic regions showed a more than 1.5 fold reduction of H3K27me3 around TSS ±5kb in MV4-11R compared to MV4-11cells. Promoter regions of HOX genes, classical targets of PRC2, revealed drastically reduced H3K27me3 enrichment in the MV4-11R cells. The H3K27me3 level at the transcriptional start site (TSS) of the ABCC1 promoter was decreased in resistant compared to sensitive cells (Fig. 6D) with increased levels of H3K4me3 and H3K27ac. As expected, we found H3K27me3 enrichments to be inversely correlated with gene expression whereas histone modifications H3K4me3 and H3K27ac, known as markers for active genes, positively correlated with gene expression in our analysis. Differentially regulated genes were characterized to be involved in protein modification/phosphorylation pathways and signaling and apoptosis.

2016-11-22 | GSE61785 | GEO

Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia.

Project description:In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells in vitro and in vivo. Low EZH2 levels resulted in derepression of HOX genes, and knockdown of HOXB7 and HOXA9 in the resistant cells was sufficient to improve sensitivity to TKIs and cytotoxic drugs. The endogenous loss of EZH2 expression in resistant cells and primary blasts from a subset of relapsed AML patients resulted from enhanced CDK1-dependent phosphorylation of EZH2 at Thr487. This interaction was stabilized by heat shock protein 90 (HSP90) and followed by proteasomal degradation of EZH2 in drug-resistant cells. Accordingly, inhibitors of HSP90, CDK1 and the proteasome prevented EZH2 degradation, decreased HOX gene expression and restored drug sensitivity. Finally, patients with reduced EZH2 levels at progression to standard therapy responded to the combination of bortezomib and cytarabine, concomitant with the re-establishment of EZH2 expression and blast clearance. These data suggest restoration of EZH2 protein as a viable approach to overcome treatment resistance in this AML patient population.

| S-EPMC6548550 | biostudies-literature

Loss of the Histone Methyltransferase EZH2 induces Resistance to Multiple Drugs in Acute Myeloid Leukemia

Project description:Here, we analyzed global gene expression changes that were associated with drug resistance in Acute Myeloid Leukemia using the Affymetrix microarray platform.

2016-11-22 | GSE61715 | GEO

Loss of the Histone Methyltransferase EZH2 induces Resistance to Multiple Drugs in Acute Myeloid Leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-11-22 | GSE61786 | GEO

Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer

Project description:This SuperSeries is composed of the following subset Series: GSE41651: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [expression] GSE41652: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [ChIP-seq] Refer to individual Series

2012-11-15 | E-GEOD-41653 | biostudies-arrayexpress

Inhibition of histone methyltransferase EZH2 in Schistosoma mansoni by GSK343 decreases the expression of genes implicated in DNA replication and ncRNA metabolism

Project description:Schistosomiasis is a chronic and debilitating disease caused by a trematode of the genus Schistosoma. The current strategy for the control of the disease involves treatment with Praziquantel, the only available drug. The development of new drugs is therefore a top priority. Drugs that inhibit histone modifying enzymes have been used in cancer, altering gene expression, replication, repair and DNA recombination. Schistosoma parasites have some characteristics similar to malignant tumors, such as intense cell division and high levels of metabolic activity. Here we evaluate in Schistosoma mansoni the effect of GSK343, an inhibitor of the histone methyltransferase EZH2 that had been shown to arrest or reduce the growth of human cancer cells. We show that GSK343 causes damage to the parasite tegument and reduces egg laying in vitro, concomitant with a decrease in levels of H3K27me3, the histone mark put in place by EZH2. RNA-seq and proteomic analyses of treated parasites showed changes in the expression of hundreds of genes involved in important metabolic processes. In females, a marked decrease was observed in the expression of genes related to processes such as DNA replication and noncoding RNA metabolism. In conclusion, the histone methyltransferase EZH2 seems to be a promising novel drug target against schistosomiasis.

2018-11-23 | PXD010342 | Pride

Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2

Project description:Inhibition of H3K27 methyltransferase EZH2 enhances osteogenic commitment of human mesenchymal progenitors and Ezh2 inactivation in mouse calvarial cells induces a post-proliferative state concomitant with increased production of a bone-related mineralizing extra-cellular matrix.

2015-09-30 | GSE73075 | GEO

Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.

2015-01-20 | E-GEOD-54979 | biostudies-arrayexpress

EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

Project description:Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We demonstrate that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracted FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induced robust MYC(N) degradation and inhibited tumor cell growth in MYC(N) driven neuroblastoma and small cell lung cancer. These findings unveil the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.

2022-02-17 | PXD029652 | Pride

Histone Methyltransferase Ezh2 Controls Cell Adhesion and Migration through Direct Methylation of the Extra-Nuclear Protein-Talin

Project description:Previously, we suggested a cytosolic role for the histone-methyltransferase Ezh2 in regulating lymphocyte activation, but molecular mechanisms underpinning this extra-nuclear function remained unclear. Here we show that Ezh2 regulates integrin-signaling and adhesion dynamics of neutrophils and dendritic cells. Ezh2 deficiency impaired integrin-dependent transendothelial migration of innate leukocytes and restricted disease progression in an animal model of multiple sclerosis. Direct methylation of talin, a key regulatory molecule in cell migration, by Ezh2 disrupted talin binding to F-actin and thereby promoted adhesion structure turnover. This regulatory effect was abolished by targeted disruption of Ezh2 interactions with Vav1. Our studies reveal a novel extra-nuclear function for Ezh2 in regulating adhesion dynamics with implications for leukocyte migration, immune responses and potentially pathogenic processes. Control and Ezh2-deficient bone marrow derived immature and mature dendritic cells were analyzed in triplicates

2015-03-09 | E-GEOD-60146 | biostudies-arrayexpress

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