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

Author:

Malone Clare F.123ORCID,Mabe Nathaniel W.123ORCID,Forman Alexandra B.12ORCID,Alexe Gabriela123ORCID,Engel Kathleen L.12ORCID,Chen Ying-Jiun C.45ORCID,Soeung Melinda123ORCID,Salhotra Silvi1,Basanthakumar Allen1,Liu Bin45,Dent Sharon Y. R.45ORCID,Stegmaier Kimberly1236ORCID

Affiliation:

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

2. Broad Institute of MIT and Harvard, Cambridge, MA, USA.

3. Harvard Medical School, Boston, MA, USA.

4. Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

5. The Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

6. Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

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