Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq I]
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ABSTRACT:
PROVIDER: PRJNA489231 | ENA |
REPOSITORIES: ENA
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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
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 | GSE133308 | GEO
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 | GSE119424 | GEO
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
Project description:Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death
| PRJNA492132 | ENA
Project description:Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death (ChIP-seq)
| PRJNA632890 | ENA
Project description:Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq II]
| PRJNA492133 | ENA
Project description:Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq III]
| PRJNA551030 | ENA
Project description:Chordoma is a primary bone cancer with no approved therapy. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors (TFs). In chordoma, we find that T is associated with a 1.5-Mb region containing “super-enhancers” and is the most highly expressed super-enhancer-associated TF. Strikingly, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. Together, these data demonstrate small-molecule targeting of brachyury TF addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.
2019-01-20 | GSE121843 | GEO
Project description:Chordoma is a primary bone cancer with no approved therapy. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors (TFs). In chordoma, we find that T is associated with a 1.5-Mb region containing “super-enhancers” and is the most highly expressed super-enhancer-associated TF. Strikingly, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. Together, these data demonstrate small-molecule targeting of brachyury TF addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.
2019-01-20 | GSE121845 | GEO