A novel synthetic jumonji H3K27 demethylase inhibitor GSK-J4 exert immunosuppressive activities
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE79898 | GEO | 2016/09/09
SECONDARY ACCESSION(S): PRJNA317354
REPOSITORIES: GEO
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Project description:Analysis of Multiple Myeloma Cell lines JJN-3 and RPMI gene expression following treated with GSK-J4 or Bortezomib
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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.
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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.
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Project description:Purpose: The goals of our study were to identify downstream pathway regulated by GSK-J4 in lung adenocarcinoma Methods: RNAs isolated from GSK-J4-treated or untreated lung adenocarcinoma (HCC827, H23 and A549) were analyzed by using an Illumina Nextseq500 Conclusions: Our study represents the first detailed transcriptomic analysis of effects of GSK-J4 in lung adenocarcinoma.
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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
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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.
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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.
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Project description:The effects of a histone demethylase inhibitor, GSK-J4, and L-ascorbic acid for the transcriptome in female ES cells were analyzed by RNA-sequence. Total RNA was used for high-throughput sequence with Illumina HiSeq 2500 and mapped to mm10. Total RNA profile
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