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The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE211355 | GEO | 2024/04/19

REPOSITORIES: GEO

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Similar Datasets

The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma [ATAC-Seq]

Project description:Pediatric cancers are frequently driven by fusion or amplification events that result in aberrant transcription factor activity. As transcription factors themselves remain challenging to target, an emerging therapeutic approach for these cancers is to target epigenetic complexes that help maintain oncogenic transcriptional programs. It is therefore critical to identify the complete set of epigenetic modulators maintaining the oncogenic epigenetic landscape of pediatric cancers. Here, we used functional genomic screens to identify epigenetic complexes critical for viability in cell line models of MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We identified multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies in MYCN-amplified neuroblastoma. Integrating ChIP-seq, ATAC-seq, and RNA-seq with targeted protein-degradation and gene editing tools, we characterized the DNA recruitment sites of the SAGA complex in neuroblastoma, and the consequences of SAGA complex lysine acetyltransferase (KAT) activity loss on histone acetylation and gene expression. We demonstrate that loss of SAGA KAT activity suppresses MYC and MYCN gene expression programs and impairs cell cycle progression. Further, we showed that the SAGA complex is pharmacologically targetable with a KAT2A/KAT2B proteolysis targeting chimera molecule that demonstrated significant activity in vitro and in vivo. Our findings expand our understanding of the histone-modifying complexes that maintain the oncogenic transcriptional state in this disease and suggest therapeutic potential for inhibitors of SAGA KAT activity in MYCN-amplified neuroblastoma.

2024-04-19 | GSE211954 | GEO

The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma [ChIP-Seq]

Project description:Pediatric cancers are frequently driven by fusion or amplification events that result in aberrant transcription factor activity. As transcription factors themselves remain challenging to target, an emerging therapeutic approach for these cancers is to target epigenetic complexes that help maintain oncogenic transcriptional programs. It is therefore critical to identify the complete set of epigenetic modulators maintaining the oncogenic epigenetic landscape of pediatric cancers. Here, we used functional genomic screens to identify epigenetic complexes critical for viability in cell line models of MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We identified multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies in MYCN-amplified neuroblastoma. Integrating ChIP-seq, ATAC-seq, and RNA-seq with targeted protein-degradation and gene editing tools, we characterized the DNA recruitment sites of the SAGA complex in neuroblastoma, and the consequences of SAGA complex lysine acetyltransferase (KAT) activity loss on histone acetylation and gene expression. We demonstrate that loss of SAGA KAT activity suppresses MYC and MYCN gene expression programs and impairs cell cycle progression. Further, we showed that the SAGA complex is pharmacologically targetable with a KAT2A/KAT2B proteolysis targeting chimera molecule that demonstrated significant activity in vitro and in vivo. Our findings expand our understanding of the histone modifying complexes that maintain the oncogenic transcriptional state in this disease and suggest therapeutic potential for inhibitors of SAGA KAT activity in MYCN-amplified neuroblastoma.

2024-04-19 | GSE211953 | GEO

The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma [RNA-Seq]

Project description:Pediatric cancers are frequently driven by fusion or amplification events that result in aberrant transcription factor activity. As transcription factors themselves remain challenging to target, an emerging therapeutic approach for these cancers is to target epigenetic complexes that help maintain oncogenic transcriptional programs. It is therefore critical to identify the complete set of epigenetic modulators maintaining the oncogenic epigenetic landscape of pediatric cancers. Here, we used functional genomic screens to identify epigenetic complexes critical for viability in cell line models of MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We identified multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies in MYCN-amplified neuroblastoma. Integrating ChIP-seq, ATAC-seq, and RNA-seq with targeted protein-degradation and gene editing tools, we characterized the DNA recruitment sites of the SAGA complex in neuroblastoma, and the consequences of SAGA complex lysine acetyltransferase (KAT) activity loss on histone acetylation and gene expression. We demonstrate that loss of SAGA KAT activity suppresses MYC and MYCN gene expression programs and impairs cell cycle progression. Further, we showed that the SAGA complex is pharmacologically targetable with a KAT2A/KAT2B proteolysis targeting chimera molecule that demonstrated significant activity in vitro and in vivo. Our findings expand our understanding of the histone modifying complexes that maintain the oncogenic transcriptional state in this disease and suggest therapeutic potential for inhibitors of SAGA KAT activity in MYCN-amplified neuroblastoma.

2024-04-19 | GSE211354 | GEO

The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma

Project description:The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma

| PRJNA869945 | ENA

The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma [ATAC-Seq]

Project description:The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma [ATAC-Seq]

| PRJNA873047 | ENA

The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma [RNA-Seq]

Project description:The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma [RNA-Seq]

| PRJNA869946 | ENA

The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma [ChIP-Seq]

Project description:The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma [ChIP-Seq]

| PRJNA873048 | ENA

Targeting EZH2 in MYCN-amplified Neuroblastoma

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

2017-12-02 | GSE85432 | GEO

AhR promotes dedifferentiation in MYCN amplified neuroblastoma

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

2023-10-10 | GSE224391 | GEO

The super elongation complex drives transcriptional addiction in <i>MYCN</i>-amplified neuroblastoma.

Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet, how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL-2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.

| S-EPMC10058231 | biostudies-literature

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