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KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [CUT&TAG]

ABSTRACT: KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [CUT&TAG]

PROVIDER: PRJNA758115 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15634900_1.fastq.gz	Fastqsanger.gz
	SRR15634900_2.fastq.gz	Fastqsanger.gz
	SRR15634901_1.fastq.gz	Fastqsanger.gz
	SRR15634901_2.fastq.gz	Fastqsanger.gz
	SRR15634886_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [RNA-seq]

Project description:The H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and is essential to neuroblastoma cell survival. While the KDM6B inhibitor, GSK-J4, has shown activity in in vitro and in vivo preclinical models, the mechanism of action remains poorly defined. We demonstrate that genetic and pharmacologic inhibition of KDM6B downregulates the pRB-E2F transcriptome and MYCN expression. Chemical genetic analyses show that high expression of the E2F transcriptome is positively correlated with sensitivity of cancer cells to GSK-J4. Mechanistically, inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and GSK-J4. A gene signature targeted by KDM6B inhibition is associated with poor survival of patients with neuroblastoma regardless of the MYCN status. These data indicate that KDM6B activity promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.

2021-10-29 | GSE149537 | GEO

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [ATAC-Seq]

2021-10-29 | GSE149519 | GEO

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [CUT&TAG]

2021-10-29 | GSE182884 | GEO

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma

Project description:KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma

| PRJNA628997 | ENA

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [RNA-seq]

Project description:KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [RNA-seq]

| PRJNA628998 | ENA

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [ATAC-Seq]

Project description:KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma [ATAC-Seq]

| PRJNA628968 | ENA

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma.

Project description:The H3K27me2/me3 histone demethylase KDM6B is essential to neuroblastoma cell survival. However, the mechanism of KDM6B action remains poorly defined. We demonstrate that inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and the KDM6 inhibitor GSK-J4. These data indicate that KDM6B promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.

| S-EPMC8664842 | biostudies-literature

Targeting CDK4/6 impairs RB1/E2F activity to overcome the resistance to selinexor in Nature killer/T-cell lymphoma

Project description:XPO1 is frequently overexpressed in multiple hematological malignancies, highlighting the attractiveness of targeting XPO1 as a therapeutic strategy. However, the therapeutic potential of XPO1 inhibition in NKTL was still not well documented. Here, we demonstrated that XPO1 is highly expressed in NKTL and is correlated with poor prognosis, suggesting that XPO1 is a potential target in NKTL. In addition, we identified YY1 as a transcriptional factor that bound to XPO1 promoter to activate its expression. Functional studies revealed that pharmacological inhibition of XPO1 using selinexor effectively blocks CDK4/6-pRB-E2F-c-Myc signaling, resulting in cell cycle arrest and apoptosis in sensitive cells. Transcriptomic analysis identified that dysfunction in cell cycle machinery may contribute to selinexor resistance, as resistant cells restore the expression of cycle-related genes to evade cell death. High-throughput screening utilizing a panel of 130 cell cycle inhibitors identified CDK4/6 inhibitors as sensitizers to selinexor in resistant cells. Mechanistically, the combination of CDK4/6 inhibitors and selinexor led to an enhanced inhibition of pRB-E2F-c-Myc signaling. Additionally, compassionate use of selinexor in combination with chemotherapy (gemcitabine, oxaliplatin) in three Refectory/Relapsed (R/R) NKTL patients achieved favorable clinical outcomes. Our data unveil a novel mechanism by which XPO1 inhibition blocks CDK4/6-pRb-E2F-c-Myc signaling, providing a rationale for the combination of CDK4/6 with XPO1 inhibitors for NKTL treatment.

2025-05-13 | GSE230615 | GEO

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma

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

2021-10-29 | GSE149539 | GEO

Palbociclib interferes with origin firing in a pRb independent manner

Project description:Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, promoting needs to understand more about the mechanism of inhibitors beyond pRb. Our study demonstrates here for the first time how palbociclib impairs the origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA without any induced cell cycle arrest. Furthermore, palbociclib treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of proteins of the Pre-initiation complex (Pre-IC) on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and on its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib to target genomic instability towards pRb deficient patient

2023-07-01 | GSE180530 | GEO

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