Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

GSK-J4 and suppression of the H3K27 demethylase UTX specifically activates expression of ATF4 and its target genes independently of PERK-eIF2α phosphorylation

ABSTRACT: UTX/KDM6A encodes a major histone H3 lysine 27 (H3K27) demethylase which is frequently mutated in various types of cancers. Although UTX appears to play a crucial role in cancer, its mechanisms remain poorly understood. Here we found that a specific pharmacological inhibitor of H3K27 demethylases, GSK-J4, induces expression of the ATF4 (transcription activating factor 4) protein and its downstream target genes (e.g. PCK2, CHOP, REDD1, CHAC1 and TRIB3), and activates autophagy-related gene products (LC3A, LC3B and ATG5-ATG12). ATF4 induction by GSK-J4 did not entail either ATF6α processing or an increase of PERK and eIF2α serine 51 phosphorylation, indicating that this action is not triggered by canonical endoplasmic reticulum (ER) stress. No changes in expression levels of the endogenous ATF4 mRNA and exogenously expressed ATF4 proteins driven by the CMV promoter were detected, suggesting that the induction is not due to either transcriptional or post-translational regulation of ATF4. Although GSK-J4 efficiently induces apoptosis, it is unlikely that the induction is due to activation of the ATF4-CHOP axis. By using gene expression profiling experiments in conjunction with CRISPR editing and stable re-expression of UTX, we found that UTX specifically suppresses expression of ATF4 target genes. These findings highlight not only that GSK-J4, which has been considered an anti-cancer drug, is a strong inducer of ATF4, but also that UTX is an important component of this regulation and may contribute to oncogenesis via ATF4 regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127860 | GEO | 2019/12/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

RNA-seq of GSK-J4 Treated Neuroblastoma Cell Lines

Project description:High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential with tumors refractory to retinoic acid differentiation based therapies. Here, we leverage high-throughput drug screening of epigenetic targeted therapies across a large and diverse tumor cell line panel to uncover the hypersensitivity of neuroblastoma cells to GSK-J4, a small molecule dual inhibitor of H3K27 demethylases UTX and JMJD3. Mechanistically, GSK-J4 induced neuroblastoma differentiation and ER stress with accompanying upregulation of PUMA and apoptosis induction. Retinoic acid (RA)-resistant neuroblastoma cells were sensitive to GSK-J4. Additionally, GSK-J4 was effective at blocking the growth of chemorefractory and patient-derived xenograft models of high-risk neuroblastoma in vivo. Further, GSK-J4 and RA combined to induce differentiation, ER-stress and limit the growth of neuroblastomas resistant to either drug alone. In MYCN-amplified neuroblastoma, which is the most prevalent driver gene alteration in the refractory population, PUMA induction by GSK-J4 sensitized tumors to the BCL-2 inhibitor venetoclax, demonstrating that epigenetic targeted therapies and BH3 mimetics can be rationally combined to treat high-risk subset of neuroblastoma. Therefore, H3K27 demethylation inhibition is a promising therapeutic target to treat high-risk neuroblastoma, and H3K27 demethylation can be part of rational combination therapies to induce robust anti-neuroblastoma activity.

2018-02-17 | GSE110709 | GEO

RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor

Project description:Persistent microglia activation is associated with the production and secretion of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify neurodegenerative diseases. A novel synthetic histone 3 lysine 27 (H3K27) demethylases JMJD3 inhibitor, GSK-J4, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for GSK-J4 molecular targets has not been undertaken in microglia. To study the immuno-modulatory effects of GSK-J4 on a transcriptomic level, triplicate RNA sequencing and quantitative real-time PCR analyses were performed with resting, GSK-J4, LPS and LPS+GSK-J4 challenged primary microglial (PM) and BV-2 microglial cells. Among the annotated genes, transcriptional sequencing of microglia that were treated with GSKJ4 revealed a selective effect on LPS induced gene expression in which the induction of cytokines/chemokines, interferon-stimulated genes, and prominent (transcription factors) TFs as well as previously unidentified genes that are important in inflammation was suppressed. Furthermore, we show that GSK-J4 controls important inflammatory genes targets by modulating STAT1, IRF7, and H3K27me3 level at their promoter site. These unprecedented results demonstrate the histone demethylases inhibitor GSK-J4 could have therapeutic applications for neuroinflammatory diseases.

2017-08-31 | GSE89817 | GEO

KDM6 Inhibition induces DNA Damage Response (DDR) during ESC Differentiation but not during self-renewal.

Project description:The discovery of the first histone demethylase in 2004 (LSD1/KDM1) opened new avenues for the understanding of how histone methylation impacts cellular functions. A great number of histone demethylases have been identified since, which are potentially linked to gene regulation as well as to stem cell self-renewal and differentiation. KDM6A/UTY and KDM6B/JMJD3 are both H3K27me3/2-specific histone demethylases, which are known to play a central role in regulation of posterior development, by regulating HOX gene expression. So far nothing is known about the role of histone lysine demethylases (KDMs) during early hematopoiesis. We are studying the role of KDM6A and KDM6B on self-renewal, global gene expression and on local and global chromatin states in embryonic stem cells (ESCs) and during differentiation. In order to completely abrogate KDM6 demethylase activity in ESCs we employed a specific inhibitor (GSK-J4, Kruidenier et al. 2012). Treatment of ESCs with GSK-J4 had no effect on viability and proliferation . However, ESC differentiation in the presence of GSK-J4 was completely abrogated. In conclusion we show that ESC differentiation is completely blockend in the absence of any H3K27 demethylase activity. We used microarrays to detail the global gene expression program of genes which are differentially expressed during the early differentiation of ESC derived embryoid bodies (EBs) in the presence of GSK-J4 (KDM6 Inhibitor). ESCs (R1) have been cultured and differentiated in the presence of GSK-J4 a KDM6 specific inhibitor.

2016-03-11 | E-GEOD-49886 | biostudies-arrayexpress

Chemical Inhibition of H3K27me3 demethylases during B cell differentiation

Project description:To understand the role of the H3K27me3 demethylases, UTX and JMJD3, in B cell differentiation. Naïve B cells were cultures ex vivo with LPS, IL-2,IL-5 in the presence of DMSO or GSK-J4, UTX/JMJD3 inhibitor. Plasmablasts and activated B cells were magnetically enriched after 3 days of culture.

2021-11-16 | GSE158139 | GEO

A novel synthetic jumonji H3K27 demethylase inhibitor GSK-J4 exert immunosuppressive activities

Project description:Using RNA-seq, we report that jumonji H3K27 demethylase inhibitor, GSK-J4, exerts potent anti-inflammatory effects on LPS-stimulated BV-2 microglial cells.

2016-09-09 | GSE79898 | GEO

Jumonji Demethylase Inhibitor GSK-J4 treated Multiple Myeloma JJN3 and RPMI

Project description:Analysis of Multiple Myeloma Cell lines JJN-3 and RPMI gene expression following treated with GSK-J4 or Bortezomib Total RNA extracted from cells after 6 or 24 hour treatment with either GSK-J4, GSK-J5, Bortezomib or vehicle

2016-08-21 | E-GEOD-60600 | biostudies-arrayexpress

Expression data from neuroblastoma cells treated with GSK-J4 or KTP-330

Project description:Neuroblastoma (NB) is a common pediatric malignancy tumor with poor outcome. Recent studies show that GSK-J4, an inhibitor of lysine 27 of histone 3 (H3K27) demethylases, and KTP-330, a clinically available inhibitor of XPO1 protein, are promising anti-cancer agents. However, their molecular mechanisms in neuroblastoma are still unclear. In this study, we used microarrays to analyze the global change in gene expression as a result of GSK-J4 or KTP-330 treatment in the human neuroblastoma cell line SH-SY5Y.

2022-01-22 | GSE180601 | GEO

Histone H3K27 demethylase negatively controls the memory formation of Ag-stimulated CD8+ T cells

Project description:Although the methylation status of histone H3K27 plays a critical role in CD4+ T cell differentiation and its function, the role of Utx, histone H3K27 demethylase, in the CD8+ T cell-dependent immune response remains unclear. We therefore generated T cell-specific Utx knockout (Utx KO) mice to determine the role of Utx in CD8+ T cells. Wild-type (WT) and Utx KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8+ T cells upon primary and secondary infections. There was no significant differences in the primary expansion of Ag-specific CD8+ T cells between WT and Utx KO mice. However, Utx deficiency resulted in an increased secondary expansion of Ag-specific CD8+ T cells. Adoptive transferred Utx KO CD8+ T cells resulted in increased numbers of CD127hi KLRG1lo memory precursors in the primary expansion and larger numbers of memory cells. We observed a decreased gene expression of effector-associated transcription factors, including Prdm1 encoding Blimp1, in Utx KO CD8+ T cells upon primary infection. We confirmed that the tri-methylation level of histone H3K27 in the Prdm1 gene loci in the Utx KO cells was higher than in the WT cells. The treatment of CD8+ T cells with Utx-cofactor α-ketoglutarate hampered the memory formation, while Utx-inhibitor GSK-J4 enhanced the memory formation and increased the secondary expansion in WT CD8+ T cells. These data suggest that Utx negatively controls the memory formation of Ag-stimulated CD8+ T cells by epigenetically regulating the expression of genes, including Prdm1. Based on these findings, we identified a critical link between Utx and the differentiation of Ag-stimulated CD8+ T cells upon infection

2021-08-31 | GSE119312 | GEO

Activation of the Integrated Stress Response by a Jumonji Histone Demethylase Inhibitor Induces Pro-Apoptotic Metabolic Reprogramming in Multiple Myeloma

Project description:Regulation of gene expression by chromatin modification through methylation of histone lysine residues is a dynamic, reversible process that when deregulated is associated with cancer development. In multiple myeloma, combined inhibition of the histone demethylases JARID1B, UTX and JmjD3 by the small molecule GSK-J4 prevents cellular glutamine utilization leading to amino acids deprivation, activates the integrated stress response via GCN2-dependent ATF4 activation, and induces apoptosis. This response is associated with a profound upregulation of metallothionein genes. Combined with clinical data demonstrating that overexpression of JARID1B is associated with shorter survival in multiple myeloma patients, this study highlights histone demethylases as epigenetic drug targets and places this demethylase inhibitor chemotype as having unique potential relative to established anti-myeloma treatment options. In total there are 7 different samples analyzed and one input control. Treatments are carried out with the demethylase inhibitor (or DMSO as negative control) at 6h and 48h, or with LNA targeting demethylases (or scrambled LNA) at 7 days. A negative control at 0h is included.

2015-08-21 | E-GEOD-60626 | biostudies-arrayexpress

Activation of the Integrated Stress Response by a Jumonji Histone Demethylase Inhibitor Induces Pro-Apoptotic Metabolic Reprogramming in Multiple Myeloma

2015-08-21 | GSE60626 | GEO