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SUV39H1 inhibition by Chaetocin targets stemness and oncogenic networks and synergizes with ONC201 against Diffuse intrinsic pontine gliomas [CUT&RUN]

ABSTRACT: SUV39H1 inhibition by Chaetocin targets stemness and oncogenic networks and synergizes with ONC201 against Diffuse intrinsic pontine gliomas [CUT&RUN]

PROVIDER: PRJNA934586 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23399467_1.fastq.gz	Fastqsanger.gz
	SRR23399467_2.fastq.gz	Fastqsanger.gz
	SRR23399468_1.fastq.gz	Fastqsanger.gz
	SRR23399468_2.fastq.gz	Fastqsanger.gz
	SRR23399469_1.fastq.gz	Fastqsanger.gz

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SUV39H1 inhibition by Chaetocin targets stemness and oncogenic networks and synergizes with ONC201 against Diffuse intrinsic pontine gliomas [RNA-seq]

Project description:To investigate Chaetocin impact on Diffuse intrinsic pontine gliomas treatment We then performed gene expression profiling analysis using data obtained from RNA-seq of Chaetocin treatment and SUV39H1 knockdown in SU-DIPG36 cells

2025-02-08 | GSE225027 | GEO

SUV39H1 inhibition by Chaetocin targets stemness and oncogenic networks and synergizes with ONC201 against Diffuse intrinsic pontine gliomas

Project description:SUV39H1 inhibition by Chaetocin targets stemness and oncogenic networks and synergizes with ONC201 against Diffuse intrinsic pontine gliomas

| PRJNA933586 | ENA

SUV39H1 inhibition by Chaetocin targets stemness and oncogenic networks and synergizes with ONC201 against Diffuse intrinsic pontine gliomas [RNA-seq]

Project description:SUV39H1 inhibition by Chaetocin targets stemness and oncogenic networks and synergizes with ONC201 against Diffuse intrinsic pontine gliomas [RNA-seq]

| PRJNA934587 | ENA

SUV39H1 inhibition by Chaetocin targets stemness and oncogenic networks and synergizes with ONC201 against Diffuse intrinsic pontine gliomas [CUT&RUN]

Project description:To identify potential direct targets of SUV39H1, we performed Cut&Run-seq for H3K9me3 and SUV39H1 genomic occupancy

2025-02-08 | GSE225028 | GEO

Chaetocin-mediated SUV39H1 inhibition targets stemness and oncogenic networks of diffuse midline gliomas and synergizes with ONC201.

Project description:BackgroundDiffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with extraordinarily limited treatment options and uniformly fatal prognosis. Histone H3K27M mutation is a common recurrent alteration in DIPG and disrupts epigenetic regulation. We hypothesize that genome-wide H3K27M-induced epigenetic dysregulation makes tumors vulnerable to epigenetic targeting.MethodsWe performed a screen of compounds targeting epigenetic enzymes to identify potential inhibitors for the growth of patient-derived DIPG cells. We further carried out transcriptomic and genomic landscape profiling including RNA-seq and CUT&RUN-seq as well as shRNA-mediated knockdown to assess the effects of chaetocin and SUV39H1, a target of chaetocin, on DIPG growth.ResultsHigh-throughput small-molecule screening identified an epigenetic compound chaetocin as a potent blocker of DIPG cell growth. Chaetocin treatment selectively decreased proliferation and increased apoptosis of DIPG cells and significantly extended survival in DIPG xenograft models, while restoring H3K27me3 levels. Moreover, the loss of H3K9 methyltransferase SUV39H1 inhibited DIPG cell growth. Transcriptomic and epigenomic profiling indicated that SUV39H1 loss or inhibition led to the downregulation of stemness and oncogenic networks including growth factor receptor signaling and stemness-related programs; however, D2 dopamine receptor (DRD2) signaling adaptively underwent compensatory upregulation conferring resistance. Consistently, a combination of chaetocin treatment with a DRD2 antagonist ONC201 synergistically increased the antitumor efficacy.ConclusionsOur studies reveal a therapeutic vulnerability of DIPG cells through targeting the SUV39H1-H3K9me3 pathway and compensatory signaling loops for treating this devastating disease. Combining SUV39H1-targeting chaetocin with other agents such as ONC201 may offer a new strategy for effective DIPG treatment.

| S-EPMC10995509 | biostudies-literature

SUV39H1 inhibition by Chaetocin targets stemness and oncogenic networks and synergizes with ONC201 against Diffuse intrinsic pontine gliomas

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-02-08 | GSE225029 | GEO

SUV39H1 epigenetically modulates the MCPIP1-AURKA signaling axis to enhance neuroblastoma tumorigenesis

Project description:Epigenetic regulation is a pivotal factor during neuroblastoma (NB) pathogenesis and investigations into cancer epigenetics are actively underway to identify novel therapeutic strategies for NB patients. SUV39H1, a member of the H3K9 methyltransferase family, contributing to tumorigenesis across multiple malignancies. However, its specific role in NB remains unexplored. In this study, we conducted a high-throughput screen utilizing a compound library containing 288 epigenetic drugs, leading to the identification of chaetocin as the most potent NB inhibitor by targeting SUV39H1. Genetic manipulation and therapeutic inhibition of SUV39H1 significantly impacted proliferation, migration, cell cycle phases, and apoptosis in NB cells. Concurrently, chaetocin demonstrated robust anti-tumor efficacy in vivo with tolerable toxicity. RNA-seq unveiled that SUV39H1 knockdown and inhibition down-regulated cell cycle pathways, impacting vital genes such as AURKA. Besides, MCPIP1 emerged as a novel tumor suppressor following SUV39H1 inhibition, which decreased AURKA expression in NB. In detail, SUV39H1 mediated the enrichment of H3K9me3 at the promoter region of MCPIP1, repressing the MCPIP1-mediated degradation of AURKA and facilitating the subsequent accumulation of AURKA, which revealed the oncogenic role of SUV39H1 via the SUV39H1-MCPIP1-AURKA signaling axis in NB. Therapeutic inhibition of SUV39H1 using chaetocin emerges as an effective and safe strategy for NB patients.

2024-12-10 | GSE254118 | GEO

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.

2023-05-25 | PXD036245 | Pride

Chaetocin efficacy on Dahl rat

Project description:Transcriptional profiling of left ventricular tissues of Dahl rat with or without treatment of chaetocin Three-condition experiment, Control vs. failing heart, failing heart vs. treatment with chaetocin. 3 samples mixture per each group

2016-04-01 | E-GEOD-66617 | biostudies-arrayexpress

SUV39H1 Maintains Cancer Stem Cells in Glioblastoma [RNA-seq]

Project description:Glioblastoma (GBM) is the deadliest brain cancer, driven in part by GBM stem cells (GSCs) that contribute to therapeutic resistance and tumor recurrence. Effective targeting and elimination of GSCs hold promise for preventing GBM recurrence and achieving potential cures. In this study, we explored the role of the epigenetic regulator SUV39H1 in GSC maintenance and GBM progression. We observed that SUV39H1 is upregulated in GBM samples compared to normal brain tissues. Single-cell RNA-seq data indicated that SUV39H1 is preferentially expressed in GSCs relative to non-stem GBM cells, possibly due to super-enhancer-mediated transcriptional activation. Knockdown of SUV39H1 in patient-derived GSCs impaired their proliferation and stemness. RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. Integrated ATAC-seq (assay for transposase-accessible chromatin followed by sequencing) and RNA-seq analyses demonstrated that targeting SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Treatment with chaetocin, a SUV39H1 inhibitor, mimicked the effects of SUV39H1 knockdown in GSCs and sensitized them to the GBM chemotherapy drug temozolomide (TMZ). In vivo studies using an intracranial patient-derived xenograft model showed that targeting SUV39H1 inhibited GSC-driven tumor formation in mice. Our findings identify SUV39H1 as a critical regulator of GSC maintenance and suggest that targeting SUV39H1 could disrupt GSCs and enhance the efficacy of existing chemotherapy, offering a promising strategy for improving GBM treatment outcomes.

2024-11-06 | GSE273012 | GEO

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