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Trancriptional changes upon JMJD3 and PI3K inhibition in MCF-7 cells

ABSTRACT: This study examines the effects of GSK-J4, GDC0941 and MK2206 on transcriptional changes of MCF-7 cells. The hypothesis tested was that genes that are co-downregulated by each inhibitor might be required for the induction of combination therapy-induced apoptosis. Results provided important information of the mechanisms of action of these inhibitors and revealed potential biomarkers to monitor drug response and development of drug resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74655 | GEO | 2016/11/30

SECONDARY ACCESSION(S): PRJNA301074

REPOSITORIES: GEO

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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

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

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Targeting Taxane-Platin Resistant Lung Cancers with JumonjiC Lysine Demethylase Inhibitors (RNA-Seq)

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2017-05-23 | GSE81687 | GEO

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2021-08-08 | GSE118319 | GEO

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

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

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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

Targeting Taxane-Platin Resistant Lung Cancers with JumonjiC Lysine Demethylase Inhibitors (ChIP-Seq)

Project description:Characterization of histone 3 lysine 4 and lysine 27 trimethylation changes upon development of taxane-platin drug resistance in NSCLC cells and evaluation of these histone modifications after treatment with Jumonji KDM inhibitors, JIB-04 and GSK-J4.

2017-05-23 | GSE81688 | GEO

Genome-wide ChIP-Seq from GSK-J4 or siKDM6B-treated lung adenocarcinoma cell line A549

Project description:Purpose: The goals of our study were to identify downstream pathway regulated by GSK-J4 in lung adenocarcinoma Methods: Chromatin isolated from GSK-J4- or siKDM6B-treated lung adenocarcinoma with proper controls was used to generate ChIP-Seq libraries

2021-08-08 | GSE133967 | GEO

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

Project description: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.

2019-12-31 | GSE127860 | GEO

Kdm2b promotes cell viability by enhancing DNA damage response in canine hemangiosarcoma

Project description:We found that lysine-specific demethylase 2b (Kdm2b) was highly expressed in HSA cell lines compared to normal canine endothelial cells. Silencing of Kdm2b in HSA cells resulted to increased cell death in vitro by inducing apoptosis through the inactivation of the DNA repair pathways and accumulation of DNA damage. Kdm2b silencing in tumor xenografts results to decreased tumor sizes compared to the control. Treatment of GSK-J4, a histone demethylase inhibitor, also induced apoptosis and cell death. In addition, GSK-J4 treatment decreases tumor sizes. Therefore, we demonstrate that Kdm2b acts as an oncogene in HSA by enhancing the DNA damage response. Moreover, we show that histone demethylase inhibitor GSK-J4 can be used as a therapeutic alternative to doxorubicin for HSA treatment.

2021-02-11 | GSE166540 | GEO

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