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Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE120214 | GEO | 2020/09/01

REPOSITORIES: GEO

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Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death (ChIP-seq)

Project description:Expression of the transcription factor brachyury (TBXT) is normally restricted to the embryo and its silencing is epigenetically regulated. TBXT promotes mesenchymal transition in a subset of common carcinomas, and in chordoma, a rare cancer showing notochordal differentiation, TBXT acts as a putative oncogene: we hypothesised that TBXT expression could be controlled through epigenetic inhibition to promote chordoma cell death. Screening of five human chordoma cell lines revealed that pharmacological inhibition of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (JMJD3) leads to cell death. This effect was phenocopied by the dual genetic inactivation of KDM6A/B using CRISPR/Cas9. Inhibition of KDM6A/B using a novel compound, KDOBA67, led to a genome-wide increase in repressive H3K27me3 marks, with concomitant reduction in H3K27ac, H3K9ac and H3K4me3 active marks. We show that TBXT is a KDM6A/B target gene, and that changes in the chromatin at TBXT following KDOBA67 treatment were associated with a reduction in TBXT protein levels in all models tested, including primary patient-derived cultures. KDOBA67 downregulated also the expression of a network of transcription factors critical for chordoma survival, whereas upregulated pathways were dominated by ATF4-driven stress and pro-apoptotic responses in all models. Blocking the AFT4-stress response did not prevent the suppression of TBXT and induction of cell death, but viability was increased by ectopic overexpression of TBXT, therefore implicating TBXT as potential therapeutic target of H3K27 demethylases inhibitors. Our work highlights how knowledge of normal processes in fetal development can provide insight into tumourigenesis and identify novel therapeutic approaches.

2020-09-01 | GSE150600 | GEO

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq II]

Project description:The expression of transcription factor brachyury (TBXT) is normally restricted to embryonic development and its silencing after mesoderm development is epigenetically regulated. In chordoma, a rare tumour of notochordal differentiation, TBXT acts as a putative oncogene, and we hypothesised that its expression could be contolled through epigenetic inhibition. Screening of five chordoma cell lines revealed that inhibitors of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (Jmjd3) reduce TBXT expression and lead to cell death, findings validated in primary patient-derived culture systems. Pharmacological inhibition was phenocopied by genetic inactivation of KDM4/B using CRISPR/Cas9. Transcriptional profiles in response to a novel KDM6A/B inhibitor, KDOBA67, revealed downregulation of critical genes and transcription factor networks for chordoma survival pathways, characterised by paired and homeobox genes, whereas upregulated pathways are dominated by stress, cell cycle and pro-apoptotic response pathways. This study supports previous data showing that the function of TBXT is essential for maintaining notochord cell fate and function and provides further evidence that TBXT is an oncogenic driver in chordoma. The data suggest that TBXT can potentially be targeted therapeutically by modulating epigenetic control mechanisms such as H3K27 demethylases.

2020-09-01 | GSE120210 | GEO

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq I]

2020-09-01 | GSE119424 | GEO

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq III]

2020-09-01 | GSE133308 | GEO

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death

Project description:Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death

| PRJNA492132 | ENA

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death (ChIP-seq)

Project description:Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death (ChIP-seq)

| PRJNA632890 | ENA

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq II]

Project description:Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq II]

| PRJNA492133 | ENA

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq III]

Project description:Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq III]

| PRJNA551030 | ENA

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq I]

Project description:Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq I]

| PRJNA489231 | ENA

Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells.

Project description:Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets. The prototypic JMJD3/UTX (Jumonji domain-containing protein 3) H3K27 demethylase inhibitor GSK-J4 increased global levels of the repressive H3K27me3 mark around transcription start sites of effector cytokine genes. Moreover, GSK-J4 reduced IFN-?, TNF?, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-10 levels in cytokine-stimulated NK cells while sparing their cytotoxic killing activity against cancer cells. The anti-inflammatory effect of GSK-J4 in NK cell subsets, isolated from peripheral blood or tissue from individuals with rheumatoid arthritis (RA), coupled with an inhibitory effect on formation of bone-resorbing osteoclasts, suggested that histone demethylase inhibition has broad utility for modulating immune and inflammatory responses. Overall, our results indicate that H3K27me3 is a dynamic and important epigenetic modification during NK cell activation and that JMJD3/UTX-driven H3K27 demethylation is critical for NK cell function.

| S-EPMC5818173 | biostudies-literature

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