The KAT module of the SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma.
Sci Adv
; 10(22): eadm9449, 2024 May 31.
Article
em En
| MEDLINE
| ID: mdl-38820154
ABSTRACT
Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity. Here, we used functional genomic screens to identify multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies for MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We characterized the DNA recruitment sites of the SAGA complex in neuroblastoma and the consequences of loss of SAGA complex lysine acetyltransferase (KAT) activity on histone acetylation and gene expression. We demonstrate that loss of SAGA complex KAT activity is associated with reduced MYCN binding on chromatin, suppression of MYC/MYCN gene expression programs, and impaired cell cycle progression. Further, we showed that the SAGA complex is pharmacologically targetable in vitro and in vivo with a KAT2A/KAT2B proteolysis targeting chimeric. 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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Regulação Neoplásica da Expressão Gênica
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Transativadores
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Lisina Acetiltransferases
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Proteína Proto-Oncogênica N-Myc
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Neuroblastoma
Limite:
Animals
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Humans
Idioma:
En
Revista:
Sci Adv
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos