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Transcriptomic and epigenomic profiling of H3K27me3 demethylases inhibitor GSK-J4 induced changes in colon cancer cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146679 | GEO | 2020/09/21

REPOSITORIES: GEO

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Transcriptomic and epigenomic profiling of H3K27me3 demethylases inhibitor GSK-J4 induced changes in colon cancer cells (ChIP-Seq)

Project description:H3K27me3 demethylases UTX and JMJD3 play vital roles in development and disease, including cancer. Therefore, we systematically investigated the impact of inhibition of these two demethylases using a small molecule inhibitor in colon cancer cells.

2020-09-21 | GSE146678 | GEO

Transcriptomic and epigenomic profiling of H3K27me3 demethylases inhibitor GSK-J4 induced changes in colon cancer cells (RNA-Seq)

2020-09-21 | GSE146676 | GEO

Transcriptomic and epigenomic profiling of H3K27me3 demethylases inhibitor GSK-J4 induced changes in colon cancer cells

Project description:Transcriptomic and epigenomic profiling of H3K27me3 demethylases inhibitor GSK-J4 induced changes in colon cancer cells

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Transcriptomic and epigenomic profiling of H3K27me3 demethylases inhibitor GSK-J4 induced changes in colon cancer cells (RNA-Seq)

Project description:Transcriptomic and epigenomic profiling of H3K27me3 demethylases inhibitor GSK-J4 induced changes in colon cancer cells (RNA-Seq)

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Transcriptomic and epigenomic profiling of H3K27me3 demethylases inhibitor GSK-J4 induced changes in colon cancer cells (ChIP-Seq)

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GSK-J4-Mediated Transcriptomic Alterations in Differentiating Embryoid Bodies.

Project description:Histone-modifying enzymes are key players in the field of cellular differentiation. Here, we used GSK-J4 to profile important target genes that are responsible for neural differentiation. Embryoid bodies were treated with retinoic acid (10 ?M) to induce neural differentiation in the presence or absence of GSK-J4. To profile GSKJ4-target genes, we performed RNA sequencing for both normal and demethylase-inhibited cells. A total of 47 and 58 genes were up- and down-regulated, respectively, after GSK-J4 exposure at a log2-fold-change cut-off value of 1.2 (p-value < 0.05). Functional annotations of all of the differentially expressed genes revealed that a significant number of genes were associated with the suppression of cellular proliferation, cell cycle progression and induction of cell death. We also identified an enrichment of potent motifs in selected genes that were differentially expressed. Additionally, we listed upstream transcriptional regulators of all of the differentially expressed genes. Our data indicate that GSK-J4 affects cellular biology by inhibiting cellular proliferation through cell cycle suppression and induction of cell death. These findings will expand the current understanding of the biology of histone-modifying enzymes, thereby promoting further investigations to elucidate the underlying mechanisms.

| S-EPMC5682251 | biostudies-literature

KDM6 histone demethylase inhibitor GSK-J4 induces metal and stress responses in multiple myeloma cells [GSK-J4]

Project description:Thioneins are cysteine-rich, evolutionary conserved apoproteins that regulate divalent metal homeostasis by virtue of their metal-chelation properties resulting in the ligand-bound metallothionein state. Previous studies have demonstrated a transient upregulation (102- 103-fold) of a cluster of metallothionein genes as part of a transcriptional response to a class of histone demethylase tool compounds targeting human Fe2+ dependent ketoglutarate oxygenases KDM6A (UTX) and KDM6B (JmjD3). Exposure of multiple myeloma cells to the prototypic bioactive KDM6 inhibitor GSK-J4 induces apoptotic cell death and transcriptomic profiles that are dominated by metal and metabolic stress response signatures. We here investigate the hypothesis that the metal-chelating property of GSK-J4 provides the means for transport and intracellular release of Zn2+ leading to a metallothionein transcriptomic response signature. Live cell imaging upon myeloma cell exposure to GSK-J4 shows a transient increase of intracellular free Zn2+ concentrations upon KDM6 inhibitor treatment consistent with a model of inhibitor mediated metal transport. Comparison of KDM6 inhibitor and ZnSO4 treatments in the presence or absence of metal chelators show that both treatment conditions induce different transcription factor repertoires with an overlapping MTF1 transcriptional regulation responsible for metallothionein and metal ion transport regulation.

2022-09-16 | GSE213291 | GEO

Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia.

Project description:Acute myeloid leukemia (AML) is a heterogeneous disease with poor outcomes. Despite increased evidence shows that dysregulation of histone modification contributes to AML, specific drugs targeting key histone modulators are not applied in the clinical treatment of AML. Here, we investigated whether targeting KDM6B, the demethylase of tri-methylated histone H3 lysine 27 (H3K27me3), has a therapeutic potential for AML.A KDM6B-specific inhibitor, GSK-J4, was applied to treat the primary cells from AML patients and AML cell lines in vitro and in vivo. RNA-sequencing was performed to reveal the underlying mechanisms of inhibiting KDM6B for the treatment of AML.Here we observed that the mRNA expression of KDM6B was up-regulated in AML and positively correlated with poor survival. Treatment with GSK-J4 increased the global level of H3K27me3 and reduced the proliferation and colony-forming ability of primary AML cells and AML cell lines. GSK-J4 treatment significantly induced cell apoptosis and cell-cycle arrest in Kasumi-1 cells, and displayed a synergistic effect with cytosine arabinoside. Notably, injection of GSK-J4 attenuated the disease progression in a human AML xenograft mouse model in vivo. Treatment with GSK-J4 predominantly resulted in down-regulation of DNA replication and cell-cycle-related pathways, as well as abrogated the expression of critical cancer-promoting HOX genes. ChIP-qPCR validated an increased enrichment of H3K27me3 in the transcription start sites of these HOX genes.In summary, our findings suggest that targeting KDM6B with GSK-J4 has a therapeutic potential for the treatment of AML.

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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

Inhibitor of H3K27 demethylase JMJD3/UTX GSK-J4 is a potential therapeutic option for castration resistant prostate cancer.

Project description:Androgen receptor (AR) mediates initiation and progression of prostate cancer (PCa); AR-driven transcription is activated by binding of androgens to the ligand-binding domain (LBD) of AR. Androgen ablation therapy offers only a temporary relief of locally advanced and metastatic PCa, and the disease eventually recurs as a lethal castration-resistant PCa (CRPC) as there is no effective treatment for CRPC patients. Thus, it is critical to identify novel targeted and combinatorial regimens for clinical management of CRPC. Reduction of the repressive epigenetic modification H3K27me2/3 correlates with PCa aggressiveness, while corresponding demethylases JMJD3/UTX are overexpressed in PCa. We found that JMJD3/UTX inhibitor GSK-J4 reduced more efficiently proliferation of AR-?LBD cells (CRPC model) compared with isogenic AR-WT cells. Inhibition of JMJD3/UTX protects demethylation of H3K27Me2/3, thus reducing levels of H3k27Me1. We observed that the reduction dynamics of H3K27Me1 was faster and achieved at lower inhibitor concentrations in AR-?LBD cells, suggesting that inhibition of JMJD3/UTX diminished proliferation of these cells by hindering AR-driven transcription. In addition, we observed synergy between GSK-J4 and Cabazitaxel, a taxane derivative that is approved for CRPC treatment. Collectively, our results point at the H3K27 demethylation pathway as a new potential therapeutic target in CRPC patients.

| S-EPMC5617492 | biostudies-literature

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