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KDM4 histone lysine demethylases maintain the adrenergic core regulatory circuitry programed by MYCN in neuroblastoma

ABSTRACT: KDM4 histone lysine demethylases maintain the adrenergic core regulatory circuitry programed by MYCN in neuroblastoma

PROVIDER: PRJNA853346 | ENA |

REPOSITORIES: ENA

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KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [RNA-seq]

Project description:A small set of interconnected lineage-specific transcription factors (TFs) form a core regulatory circuitry (CRC) that establishes and maintains cell identity and grants selective dependencies of distinct cancer types. However, effective therapies to targeting CRC TFs remain lacking. Here, we show that the best-in-class KDM4 inhibitor QC6352 has a potent anticancer activity in MYCN-driven high-risk neuroblastoma and significantly represses the CRC TFs including MYCN, HAND2, ASCL1, PHOX2B by disrupting the super-enhancers that dominate the expression of CRC TFs. Furthermore, we have developed a combination therapy by integrating QC6352 into cytotoxic chemotherapy, which leads to a complete response of MYCN amplified tumors and a better animal survival. This study reveals that targeting histone lysine demethylase 4 family may transform into a therapeutic strategy in clinic for cancers driven by CRC TFs.

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KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [Cut&Tag]

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Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma [RNA-seq]

Project description:Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that requires long-term intensive multimodal therapies. Less than 50% survival rate of high-risk patients has prompted active and extensive studies to seek more effective therapies against MNA neuroblastomas but with few successes. We show that MYCN transdifferentiates the neuroblastoma cells from mesenchymal state to adrenergic state accompanied with induction of histone lysine demethylase 4 family members (KDM4A-C), all of which act in concert to control the expression of MYCN and adrenergic core regulatory transcription factors (CRC TF). Pharmacologic inhibition of KDM4 blocks expression of MYCN and adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against MNA neuroblastomas by inducing differentiation, apoptosis and type I interferon response. KDM4 inhibition in combination with chemotherapy leads to complete tumor response of MNA xenografts, without overt toxicity in animals. Thus, KDM4 blockade may be a transformative strategy to target the dependency of adrenergic CRC TFs in MNA neuroblastomas.

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Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma [ATAC-seq]

Project description:Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that requires long-term intensive multimodal therapies. Despite this, high-risk patients have a poor survival rate, which has prompted extensive studies aimed at identifying more effective therapies against neuroblastomas with MNA. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein can promote a cellular state switch in mesenchymal cells to an adrenergic state. This cellular state transition is accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C), which act in concert to control the expression of MYCN and adrenergic core regulatory transcription factors (CRC TF). Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation, apoptosis, and a type I interferon response. Further, KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA, without overt toxicity in animals. Thus, KDM4 blockade may be a novel and transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.

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KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [ATAC-seq]

Project description:KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [ATAC-seq]

| PRJNA690789 | ENA

KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [ChIP-seq]

Project description:KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [ChIP-seq]

| PRJNA690790 | ENA

KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [RNA-seq]

Project description:KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [RNA-seq]

| PRJNA690792 | ENA

KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [Cut&Tag]

Project description:KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [Cut&Tag]