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

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

PROVIDER: PRJNA830454 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18890729_1.fastq.gz	Fastqsanger.gz
	SRR18890729_2.fastq.gz	Fastqsanger.gz
	SRR18890730_1.fastq.gz	Fastqsanger.gz
	SRR18890730_2.fastq.gz	Fastqsanger.gz
	SRR18890731_1.fastq.gz	Fastqsanger.gz

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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]

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

| PRJNA816823 | ENA

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

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

| PRJNA816824 | ENA

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 [ChIP-Seq, 2]

2022-09-06 | GSE198752 | 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 [CUT&RUN, 2]

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

| PRJNA816825 | ENA

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

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

| PRJNA816826 | ENA

BioID HEK293T PAX3-FOXO1 proximity labelling

Project description:PAX3-FOXO1 is a fusion transcription factor that is the main driver of tumorigenesis leading to the development of alveolar rhabdomyosarcoma (aRMS). Since aRMS cells are addicted to PAX3-FOXO1 activity, the fusion protein also represents a major target for therapeutic interference, which is however challenging as transcription factors usually cannot be inhibited directly by small molecules. Hence, characterization of the biology of PAX3-FOXO1 might lead to the discovery of new possibilities for an indirect inhibition of its activity. Here, our goal was to characterize the proteomic neighborhood of PAX3-FOXO1 and to find candidates potentially affecting its activity and tumor cell viability. Towards this aim, we expressed BirA fused versions of PAX3-FOXO1 (N- and C-terminal) in HEK293T cells under presence of biotin. In the control setup, we expressed the BirA enzyme alone. After Streptavidin purification of biotinylated proteins, we performed mass spectrometry and quantified relative abundances compared to control conditions. This enabled us to determine PAX3-FOXO1 proximal proteins, which we investigated further in orthogonal endogenous systems.

2021-09-16 | PXD022187 | Pride

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