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

Clare F Malone1,2,3, Nathaniel W Mabe1,2,3, Alexandra B Forman1,2

  • 1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Science Advances
|May 31, 2024
PubMed

Insights

Researchers found that the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex is crucial for MYCN-amplified neuroblastoma. Inhibiting the SAGA complex

Area of Science:

  • * Molecular Biology
  • * Cancer Genomics
  • * Epigenetics

Background:

  • * Pediatric cancers, particularly MYCN-amplified neuroblastoma, are driven by abnormal transcription factor activity.
  • * The Spt-Ada-Gcn5-acetyltransferase (SAGA) complex is a key transcriptional coactivator involved in gene regulation.

Purpose of the Study:

  • * To identify genes within the SAGA complex essential for MYCN-amplified neuroblastoma.
  • * To investigate the role of SAGA complex lysine acetyltransferase (KAT) activity in neuroblastoma.
  • * To explore the therapeutic potential of targeting the SAGA complex in this disease.

Main Methods:

  • * Functional genomic screens were employed to identify SAGA complex dependencies.
  • * DNA immunoprecipitation and chromatin analysis were used to map SAGA recruitment sites.
  • * Histone acetylation, gene expression, and cell cycle progression were assessed upon loss of SAGA KAT activity.
  • * In vitro and in vivo studies evaluated the efficacy of SAGA complex inhibitors.

Main Results:

  • * The SAGA complex was identified as a selective dependency in MYCN-amplified neuroblastoma.
  • * Loss of SAGA KAT activity led to reduced MYCN binding, suppressed MYC/MYCN gene programs, and impaired cell cycle progression.
  • * The SAGA complex was shown to be pharmacologically targetable using KAT2A/KAT2B proteolysis targeting chimeras.

Conclusions:

  • * The SAGA complex plays a critical role in maintaining the oncogenic transcriptional state in MYCN-amplified neuroblastoma.
  • * Targeting SAGA KAT activity presents a promising therapeutic strategy for MYCN-amplified neuroblastoma.

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