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SUMOylation controls Daunorubicin-regulated gene expression in the Acute Myeloid Leukemia cell line HL-60

ABSTRACT: SUMOylation, a post-translational modification of the ubiquitin family plays key roles in Acute Myeloid Leukemias response to therapies, in particular through the regulation of gene expression. We have investigated here how inhibition of SUMOylation with ML-792 affects gene daunorubicine (DNR-)-regulated gene expression. We found that inhibition of SUMOylation limits DNR-induce up- or down-regulation of gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198982 | GEO | 2023/06/23

REPOSITORIES: GEO

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SUMOylation regulates daunorubicin-induced changes in the long-range interactions between NFKB2 promoter and distant genomic regions in HL-60 cells

Project description:SUMOylation, a post-translational modification of the ubiquitin family plays key roles in Acute Myeloid Leukemias response to therapies, in particular through the regulation of gene expression. We have found that the NFKB2 gene is rapidly induced by DNR in the HL-60 cell line and inhibition of SUMOylation limits is induction. To decipher how SUMOylation controls DNR-induced NFKB2 expression, we analyzed the dynamic of the 3D conformation of the NFKB2 gene using Circularized Chromosome Conformation Capture (4C). We found that the NFKB2 promoter interacts with four distal regions. DNR induced a loss of one of the interaction and the gain of a new interaction. Inhibition of SUMOylation with ML-792 did not affect the interactions between NFKB2 promoter and distal genomic regions. However, inhibition of SUMOylation prevented DNR-regulated changes in the 3D architecture of the locus.

2023-06-23 | GSE198981 | GEO

SUMO2/3 CHIP-Seq in HL-60 cells treated or not with cytarabine or daunorubicine

Project description:SUMOylation, a post-translational modification of the ubiquitin family plays key roles in Acute Myeloid Leukemias response to therapies, in particular through the regulation of gene expression. We have investigated here how daunorubicine (DNR) and cytarabine (Ara-C), the two main drugs used for Acute Myeloid Leukemia treatment, affect the distribution of SUMO on chromatin in the HL-60 cell lines. We found that DNR but not Ara-C leads to a massive decrease in the presence of SUMOylated proteins on the chromatin, in particular at promoters and enhancers, where they are enriched.

2023-06-23 | GSE198985 | GEO

RNA-Seq analysis of HL-60 AML cells resistant to daunorubicin or cytarabine

Project description:The Acute Myeloid Leukemia cell line HL-60 was rendered resistant to daunorubicin (DNR) or cytarabine (Ara-C) by continuous exposure to the drug up to concentrations of 30nM for DNR and 100nM for Ara-C. Transcriptomic analysis were then performed by RNA-Seq to compare the cell lines

2022-01-08 | GSE193094 | GEO

Probing the Roles of SUMOylation in Cancer Cell Biology Using a Selective SAE inhibitor

Project description:Small ubiquitin-like modifier (SUMO) family proteins regulate target protein functions by post-translational modification. However, a potent and selective inhibitor to target the SUMO pathway has been lacking. Here we describe ML-792, the first mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, which leads to reduced cancer cell proliferation. Moreover, induction of the MYC oncogene increased the ML-792 mediated viability effect in cancer cells, indicating potential application of SAE inhibitors in MYC-amplified tumors. Using ML-792, we further explored the critical roles of SUMOylation in mitotic progression and chromosome segregation. Furthermore, expression of an SAE catalytic subunit (UBA2) mutant S95N/M97T rescued SUMOylation loss and the mitotic defect induced by ML-792, confirming the selectivity of ML-792. As a potent and selective SAE inhibitor, ML-792 provides rapid loss of endogenously SUMOylated proteins allowing for novel insights into SUMO biology.

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SUMO-2/3 ChIP-Seq in HL-60 cells treated or not with Daunorubicin, Cytarabin and the Nox inhibitor VAS2870

Project description:Acute Myeloid Leukemia cell line HL-60 were treated with 1 M daunorubicin (DNR) or 2M cytarabin (Ara-C) or 1 M DNR + 10 M VAS2870 (NADPH oxidase inhibitor) for 2 hours. ChIP-Seq experiments were carried out with SUMO-2/3 antibodies. Immunoprecipitated DNA and corresponding inputs from 3 independent experiments were pooled and processed for deep-sequencing (Hi-SEq 2000, Illumina).

2023-12-30 | E-MTAB-4947 | biostudies-arrayexpress

Gene profiling changes in mouse bone marrow derived macrophages upon SUMOylation inhibition

Project description:SUMOylation, a posttranslational modification, regulates protein function by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins. Here we use ML-792, a selective SUMO-activating enzyme (SAE) inhibitor, to inhibit global SUMOylation in macrophages derived from bone marrow of C57BL/6 mice. Mouse bone marrow cells isolated from 6–10 weeks C57BL/6 mice were cultured in IMDM medium supplemented with 10% (vol/vol) FBS and 10 ng/mL of macrophage colony-stimulating factor (M-CSF). After 6–8 days of differentiation, the cells were treated with vehicle or ML-792 at 0.5 μM for 24 h. Total RNA was purified using miRNeasy RNA isolation kit (Qiagen) then Ribo-Zero RNA-seq was performed.

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SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites [array]

Project description:Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin occupancy and target gene expression of GR in a locus-selective manner, but the mechanism of regulation has remained elusive. Here, we identify the protein network around chromatin-bound GR by using selective isolation of chromatin-associated proteins and show that the network is affected by receptor SUMOylation, with several nuclear receptor coregulators and chromatin modifiers preferring interaction with SUMOylation-deficient GR and proteins implicated in transcriptional repression preferring interaction with SUMOylation-competent GR. This difference is reflected in our chromatin binding, chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in binding and opening chromatin at glucocorticoid-regulated enhancers and inducing expression of target loci. Blockage of SUMOylation by a SUMO-activating enzyme inhibitor (ML-792) phenocopied to a large extent the consequences of GR SUMOylation deficiency on chromatin binding and target gene expression. Our results thus show that SUMOylation modulates the specificity of GR by regulating its chromatin protein network and accessibility at GR-bound enhancers. We speculate that many other SUMOylated TFs utilize a similar regulatory mechanism.

2021-01-08 | GSE64372 | GEO

SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites [sequencing]

2021-01-08 | GSE64301 | GEO

Genes rapidly regulated by Ara-C and DNR treatment of HL-60 AML cells and role of NADPH-oxidase derived ROS in DNR-induced gene expression

Project description:Daunorubicin (DNR) and Cytarabin (Ara-C) are the main chemotherapeutic drugs used for Acute Myeloid Leukemias (AML) treatment. However, their mode of action is not well understood. To decipher if these drug would induce rapid transcriptional reprogramming, we treated HL-60 AML cell line with DNR or Ara-C for 3 hours and carried out a transcriptomic analyses. In addition, we had shown that Reactive Oxigen Species (ROS) produced by NADPH oxidases (NOX) are involved in DNR-induced gene expression. We therefore also performed a transcriptomic analyses in HL-60 cells treated with DNR and VAS2870, an NADPH oxidase inhibitor. HL-60 cells were treated or not for 3 hours with 2 ÂµM Ara-C, 1 ÂµM DNR or 1 ÂµM DNR + 20ÂµM VAS 2870. RNAs were purified from 3 independent experiments and used to probe Affymetrix Human Gene 2.0 ST Genechips

2017-12-31 | E-MTAB-4895 | biostudies-arrayexpress

Gene expression signatures in ex vivo Cytarabine (Ara-C) and Daunorubicin (Dnr) sensitive AML samples

Project description:Wide inter-individual variation in terms of outcome and toxic side effects of treatment exist among patients with AML receiving chemotherapy with cytarabine (Ara-C) and daunorubicin (Dnr). Drug resistance and relapse are considered major causes of treatment failure. Gene expression profiling was undertaken to address possible mechanisms of Ara-C/Dnr resistance. Based on ex vivo Ara-C cytotoxicity at diagnosis, Ara-C sensitive (IC50 <3uM AraC) and Dnr sensitive samples (IC50 < 0.5 uM) (5 samples each) were included for microarray analysis. These were compared with the samples which were drug resistant ex vivo at diagnosis. Our microarray experiment resulted in indentifying differentially expressed genes under ex vivo Ara-C sensitive as well as Dnr sensitive samples compared to ex vivo Drug resistant samples.

2016-01-02 | GSE52919 | GEO

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