Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting KDM4B to disrupt the core regulatory transcription network governed by PAX3-FOXO1 in high-risk rhabdomyosarcoma [CUT&RUN]

ABSTRACT: Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3–FOXO1, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability to the PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth, disrupting the expression of CRC TFs in accordance with the alterations of PAX3–FOXO1-determining super enhancers. Combination of KDM4B inhibitor with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3–FOXO1, which may translate to a novel therapeutic approach for the high-risk RMS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157093 | GEO | 2022/09/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Targeting KDM4B to disrupt the core regulatory transcription network governed by PAX3-FOXO1 in high-risk rhabdomyosarcoma [ChIP-seq]

Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3–FOXO1, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability to the PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth, disrupting the expression of CRC TFs in accordance with the alterations of PAX3–FOXO1-determining super enhancers. Combination of KDM4B inhibitor with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3–FOXO1, which may translate to a novel therapeutic approach for the high-risk RMS.

2022-09-06 | GSE157094 | GEO

Targeting KDM4B to disrupt the core regulatory transcription network governed by PAX3-FOXO1 in high-risk rhabdomyosarcoma [ATAC-seq]

2022-09-06 | GSE157092 | GEO

Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [RNAseq_LHCN_hg19]

Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.

2022-09-06 | GSE201224 | GEO

Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [RNA-Seq]

2022-09-06 | GSE198755 | GEO

Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [CUT&Tag]

2022-09-06 | GSE198754 | GEO

Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [CUT&RUN, 2]

2022-09-06 | GSE198753 | GEO

Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [ChIP-Seq, 2]

2022-09-06 | GSE198752 | GEO

Piperacetazine directly binds to the PAX3::FOXO1 fusion protein and inhibits its transcriptional activity

Project description:The tumor-specific chromosomal translocation product, PAX3::FOXO1, is an aberrant fusion protein that plays a key role for oncogenesis in the alveolar subtype of rhabdomyosarcoma (RMS). PAX3::FOXO1 represents a validated molecular target for alveolar RMS and successful inhibition of its oncogenic activity is likely to have significant clinical applications. Even though several PAX3::FOXO1 function-based screening studies have been successfully completed, a directly binding small molecule inhibitor of PAX3::FOXO1 has not been reported. Therefore, we screened small molecule libraries to identify compounds that were capable of directly binding to PAX3::FOXO1 protein using surface plasmon resonance technology. Compounds that directly bound to PAX3::FOXO1 were further evaluated in secondary transcriptional activation assays. We discovered that piperacetazine can directly bind to PAX3::FOXO1 protein and inhibit fusion protein-derived transcription in multiple alveolar RMS cell lines. Piperacetazine inhibited anchorage-independent growth of fusion positive alveolar RMS cells but not embryonal RMS cells. Based on our findings, piperacetazine is a molecular scaffold upon which derivatives could be developed as specific inhibitors of PAX3::FOXO1. These novel inhibitors could potentially be evaluated in future clinical trials for recurrent or metastatic alveolar RMS as novel targeted therapy options.

2023-09-12 | GSE242690 | GEO

Dependence of PAX3-FOXO1 chromatin occupancy on ETS1 at important disease-promoting genes exposes new targetable vulnerability in Fusion-Positive Rhabdomyosarcoma [CUT&Run]

Project description:Rhabdomyosarcoma (RMS), a malignancy of impaired myogenic differentiation, is the most common soft tissue pediatric cancer. PAX3-FOXO1 oncofusions drive the majority of the clinically more aggressive fusion-positive rhabdomyosarcoma (FP-RMS). Recent studies have established an epigenetic basis for PAX3-FOXO1-driven oncogenic processes. However, details of PAX3-FOXO1 epigenetic mechanisms, including interactions with, and dependence on, other chromatin and transcription factors, are incompletely understood. We previously identified a novel disease-promoting epigenetic axis in RMS, involving the histone demethylase KDM3A and the ETS1 transcription factor, and demonstrated that this epigenetic axis interfaces with PAX3-FOXO1 both phenotypically and transcriptomically, including co-regulation of biological processes and genes important to FP-RMS progression. In this study, we demonstrate that KDM3A and ETS1 colocalize with PAX3-FOXO1 to enhancers of important disease-promoting genes in FP-RMS, including FGF8, IL4R, and MEST, as well as PODXL, which we define herein as a new FP-RMS-promoting gene. We show that ETS1, which is induced by both PAX3-FOXO1 and KDM3A, exists in complex with PAX3-FOXO1, and augments PAX3-FOXO1 chromatin occupancy. We further show that the PAX3-FOXO1/ETS1 complex can be disrupted by the clinically relevant small molecule inhibitor YK-4-279. YK-4-279 displaces PAX3-FOXO1 from chromatin and interferes with PAX3-FOXO1-dependent gene regulation, resulting in potent inhibition of growth and invasive properties in FP-RMS, along with downregulation of FGF8, IL4R, MEST and PODXL expression. We additionally show that, in some FP-RMS, KDM3A also increases PAX3-FOXO1 levels. Together, our studies illuminate mechanisms of action of the KDM3A/ETS1 regulatory module, and reveal novel targetable mechanisms of PAX3-FOXO1 chromatin complex regulation, in FP-RMS.

2024-10-25 | GSE279336 | GEO

Dependence of PAX3-FOXO1 chromatin occupancy on ETS1 at important disease-promoting genes exposes new targetable vulnerability in Fusion-Positive Rhabdomyosarcoma [RNA-Seq]

2024-10-25 | GSE279335 | GEO