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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164456 | GEO | 2024/03/02

REPOSITORIES: GEO

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Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma.

Project description:Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. 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 and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.

| S-EPMC10983111 | biostudies-literature

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

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

2024-03-02 | GSE240506 | GEO

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.

2024-03-04 | GSE240505 | GEO

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.

2024-03-04 | GSE240504 | GEO

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

Project description:Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma

| PRJNA1003934 | ENA

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

Project description:Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma

| PRJNA690781 | ENA

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

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

| PRJNA1003939 | ENA

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

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

| PRJNA1003931 | ENA

Lysine-specific demethylase (LSD1/KDM1A) and MYCN cooperatively repress tumor suppressor genes in neuroblastoma.

Project description:The chromatin-modifying enzyme lysine-specific demethylase 1, KDM1A/LSD1 is involved in maintaining the undifferentiated, malignant phenotype of neuroblastoma cells and its overexpression correlated with aggressive disease, poor differentiation and infaust outcome. Here, we show that LSD1 physically binds MYCN both in vitro and in vivo and that such an interaction requires the MYCN BoxIII. We found that LSD1 co-localizes with MYCN on promoter regions of CDKN1A/p21 and Clusterin (CLU) suppressor genes and cooperates with MYCN to repress the expression of these genes. KDM1A needs to engage with MYCN in order to associate with the CDKN1A and CLU promoters. The expression of CLU and CDKN1A can be restored in MYCN-amplified cells by pharmacological inhibition of LSD1 activity or knockdown of its expression. Combined pharmacological inhibition of MYCN and LSD1 through the use of small molecule inhibitors synergistically reduces MYCN-amplified Neuroblastoma cell viability in vitro. These findings demonstrate that LSD1 is a critical co-factor of the MYCN repressive function, and suggest that combination of LSD1 and MYCN inhibitors may have strong therapeutic relevance to counteract MYCN-driven oncogenesis.

| S-EPMC4546488 | biostudies-literature

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

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

2024-03-02 | GSE207035 | GEO