The KAT module of the SAGA complex maintains the oncogenic gene expression program in MYCN- amplified neuroblastoma Article Swipe
Clare F. Malone
,
Nathaniel W. Mabe
,
Alexandra B. Forman
,
Gabriela Alexe
,
Kathleen Engel
,
Ying-Jiun C. Chen
,
Melinda Soeung
,
Silvi Salhotra
,
Allen Basanthakumar
,
Bin Liu
,
Sharon Dent
,
Kimberly Stegmaier
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1126/sciadv.adm9449
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1126/sciadv.adm9449
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.
Related Topics
Concepts
Neuroblastoma
Biology
Histone
Histone acetyltransferase
Coactivator
Chromatin
Gene
Cancer research
Transcription factor
Regulation of gene expression
Gene expression
POU domain
Genetics
Cell culture
Homeobox
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1126/sciadv.adm9449
- OA Status
- gold
- Cited By
- 11
- References
- 90
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4399205824
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4399205824Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1126/sciadv.adm9449Digital Object Identifier
- Title
-
The KAT module of the SAGA complex maintains the oncogenic gene expression program in MYCN- amplified neuroblastomaWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
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2024-05-31Full publication date if available
- Authors
-
Clare F. Malone, Nathaniel W. Mabe, Alexandra B. Forman, Gabriela Alexe, Kathleen Engel, Ying-Jiun C. Chen, Melinda Soeung, Silvi Salhotra, Allen Basanthakumar, Bin Liu, Sharon Dent, Kimberly StegmaierList of authors in order
- Landing page
-
https://doi.org/10.1126/sciadv.adm9449Publisher landing page
- Open access
-
YesWhether a free full text is available
- OA status
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goldOpen access status per OpenAlex
- OA URL
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https://doi.org/10.1126/sciadv.adm9449Direct OA link when available
- Concepts
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Neuroblastoma, Biology, Histone, Histone acetyltransferase, Coactivator, Chromatin, Gene, Cancer research, Transcription factor, Regulation of gene expression, Gene expression, POU domain, Genetics, Cell culture, HomeoboxTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
11Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 8, 2024: 3Per-year citation counts (last 5 years)
- References (count)
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90Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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