Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of SP/KLF transcription regulatory network and histone deacetylases acts synergistically against H3K27M-DIPG

ABSTRACT: Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with limited therapeutic options. Frequently harboring H3K27M mutations, these tumors are resistant to Histone deacetylase inhibitors (HDACi) in clinical trials for yet unclear reasons. Given this, there is a critical need for exploring the reasons of insufficient clinical manifestations of HDACi and identifying effective combinatorial therapeutic strategy for the treatment of DIPG. To explore the possibility of combining HDACi with EC-8042, an analog of Mithramycin that blocks the DNA binding of SP/KLF factors, We performed RNA-seq in SU-DIPG-IV and SU-DIPG-XVII cells after treated with DMSO, vorinostat and combination vorinostat with EC-8042. And revealed that HDACi treatment amplifies the expression of hypoxia-responsive genes and promotes tumor invasiveness, which is efficiently counteracted by EC8042. And EC-8042 in combination with HDACi synergistically represses the expression of cell cycle-associated genes and therefore suppresses H3K27M-DIPG cell proliferation, inhibiting tumor progression in orthotopic xenograft models. Transcriptomic analysis further supports that the combination treatment drives transcriptional programs correlating with favorable prognosis in DIPG patients. Therefore, our regulome profiling in H3K27M-DIPGs has provided mechanistic insights into HDACi resistance and a proof-of-concept for novel targeting therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255013 | GEO | 2024/02/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

EC-8042 reverses the increased SP/KLFs chromatin binding caused by HDACi in H3K27M-DIPG

Project description:Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with limited therapeutic options. Frequently harboring H3K27M mutations, these tumors are resistant to Histone deacetylase inhibitors (HDACi) in clinical trials for yet unclear reasons. Given this, there is a critical need for exploring the reasons of insufficient clinical manifestations of HDACi and identifying effective combinatorial therapeutic strategy for the treatment of DIPG. To explore the possibility of combining HDACi with EC-8042, an analog of Mithramycin that blocks the DNA binding of SP/KLF factors，We performed CUT&Tag of SP1 in SU-DIPG-XVII cells after treated with DMSO, vorinostat and combination vorinostat with EC-8042. And discovered that EC-8042 reverses the increased SP/KLFs chromatin binding caused by HDACi.

2024-02-08 | GSE255012 | GEO

EC-8042 reverses the activated transcriptional programs caused by HDACi in H3K27M-DIPG

Project description:Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with limited therapeutic options. Frequently harboring H3K27M mutations, these tumors are resistant to Histone deacetylase inhibitors (HDACi) in clinical trials for yet unclear reasons. Given this, there is a critical need for exploring the reasons of insufficient clinical manifestations of HDACi and identifying effective combinatorial therapeutic strategy for the treatment of DIPG. To explore the possibility of combining HDACi with EC-8042, an analog of Mithramycin that blocks the DNA binding of SP/KLF factors，We performed ChIP-seq of H3K27ac in SU-DIPG-XVII cells after treated with DMSO, vorinostat and combination vorinostat with EC-8042. And discovered that EC-8042 reverses the activated transcriptional programs caused by HDACi.

2024-02-08 | GSE255011 | GEO

EC-8042 reverses the gained accessibility caused by HDACi in H3K27M-DIPG

Project description:Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with limited therapeutic options. Frequently harboring H3K27M mutations, these tumors are resistant to Histone deacetylase inhibitors (HDACi) in clinical trials for yet unclear reasons. Given this, there is a critical need for exploring the reasons of insufficient clinical manifestations of HDACi and identifying effective combinatorial therapeutic strategy for the treatment of DIPG. Using ATAC-seq, we identified that HDACi cause heightened accessibility, and the HDACi-opened chromatin regions are highly enriched for SP/KLF motifs. To explore the possibility of combining HDACi with EC-8042, an analog of Mithramycin that blocks the DNA binding of SP/KLF factors，We performed ATAC-seq in SU-DIPG-XVII cells after treated with DMSO, vorinostat and combination vorinostat with EC-8042. And discovered that EC-8042 reverses the gained accessibility caused by HDACi.

2024-02-08 | GSE255010 | GEO

Histone H3 K27M mediated Regulation of Cancer Cell Stemness and Differentiation in Diffuse Intrinsic Pontine Glioma (DIPG) [RNA-seq]

Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare pediatric brain tumor with a median survival of 10-15 months. Histone H3 is mutated in 80% of DIPGs, dictating tumor location, onset, and outcome. Therapeutic resistance remains a major obstacle to preventing tumor recurrence and is in part driven by cancer stem cells (CSCs), which exhibit self-renewal properties and tumorigenic potential. In previous studies, we have identified these proliferative and tumorigenic features in aldehyde dehydrogenase positive (ALDH+) CSCs in H3K27M mutant DIPG. We hypothesize that ALDH-mediated cancer stemness and resistance may in part be driven by H3K27M. ALDH1A3 expression was reduced in CRISPR-edited DIPG cells (SU-DIPG-XIII) where the H3K27M mutation had been removed (H3K27M-KO). Furthermore, these gained differentiation characteristics and lost their neurosphere-forming potential. The parental (H3K27M) and H3K27M-KO cells were also subjected to ionizing radiation to identify genes responsible for radioresistance in histone-mutated DIPG radioresistance. Nascent transcriptomes were obtained from these cells using bromouridine labeling and capture followed by sequencing (Bru-seq).

2023-08-30 | GSE211833 | GEO

The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential [MeDIP-Seq]

Project description:Lysine 27 to methionine mutation (H3K27M) of the H3F3A gene, which encodes the variant histone H3.3, is found in the majority of Diffuse Intrinsic Pontine Gliomas (DIPGs). DIPGs are the most aggressive form of pediatric gliomas and have a median survival of <1 year from diagnosis. As H3K27M mutation is necessary but not sufficient to cause DIPGs, it is accompanied by several other mutations in tumors. However, the mechanisms by which H3K27M increases vulnerability to DIPG tumorigenesis, while expected to involve altered epigenetic regulation is unclear. Thus, in this work we built pairs of isogenic human embryonic stem cell lines with versus without this mutation, in the absence of other DIPG contributory mutations, to investigate mechanisms by which H3K27M mutation could affect cellular proliferation and differentiation and how these were related to alterations in the transcriptome, H3K27me3, and the DNA methylome. We found that H3K27M increased stem cell proliferation and interfered with differentiation, resulting in loss of most H3K27me3 and resulting in anomalous onset of expression of developmental genes during multilineage or directed differentiation. This work suggests mechanisms by which H3K27M mutation influences stem cell properties, contributing to DIPG tumorigenesis.

2021-12-31 | GSE159465 | GEO

The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential [ChIP-Seq]

2021-12-31 | GSE158143 | GEO

The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential [RNA-Seq]

2021-12-31 | GSE159070 | GEO

EZH2 is a potential therapeutic target for H3K27M mutant paediatric gliomas [RNA-Seq - mouse cell lines]

Project description:Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive brain tumour that is located in the pons and primarily affects children. Whole-exome sequencing studies have identified recurrent driver mutations in H3F3A (H3.3) and HIST1H3B (H3.1), leading to the expression of histone H3 in which lysine 27 is substituted with methionine (H3K27M) in nearly 80% of DIPGs1-5. H3K27M has been shown to inhibit Polycomb Repressive Complex 2 (PRC2) activity by binding to its catalytic subunit EZH2, and although DIPGs with H3K27M mutation show global loss of H3 with trimethylated lysine 27 (H3K27me3), several genes retain H3K27me3 (Refs. 1-8). Here, we describe a mouse DIPG model in which H3K27M potentiates tumourigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M expressing tumours require PRC2 for proliferation. Furthermore, we demonstrate that small molecule EZH2 inhibitors abolish tumour cell growth through a mechanism that is dependent on the induction of the tumour suppressor protein p16INK4A. Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets and are highly enriched for H3K27me3/PRC2/PRC1 in cells prior to H3K27M expression. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the mouse DIPG model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M positive DIPGs, and inhibition of EZH2 is as a potential therapeutic strategy for the treatment of these tumours.

2017-02-28 | GSE85385 | GEO

EZH2 is a potential therapeutic target for H3K27M mutant paediatric gliomas [RNA-Seq mouse tumors]

2017-02-28 | GSE85388 | GEO

EZH2 is a potential therapeutic target for H3K27M mutant paediatric gliomas [ChIP-Seq human cell lines]

2017-02-28 | GSE85387 | GEO