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SOX11 as guardian of epigenetic plasticity in neuroblastoma

Boekbijdrage - Boekabstract Conferentiebijdrage

Background/Introduction: Normal human development is controlled through the complex interplay of multiple transcription factors and the reshaping of epigenetic landscapes. Tumor cells can co-opt normal developmental pathways for functions that are linked to tumor progression and may become addicted to survival mechanisms controlled by developmental master regulators. Neuroblastoma (NB), the most common extra-cranial tumor in childhood, arises from the sympatho-adrenergic lineage during normal embryonic development. The genomic landscape of NB is characterized by a low mutational burden and highly recurrent copy number changes. Consequently, these copy number alterations affecting lineage-dependency factors in the sympatho-adrenal lineage might be strong candidates for NB cell addiction. The study of such oncogenic lineage-dependency factors is considered of strong translational value as they could represent highly selective drug targets compared to conventional cytotoxic therapy.Aims: We aimed to scrutinize DNA copy number profiles for gains or amplifications of putative lineage-dependency transcription factors involved in the epigenetic landscape and development of NB.Methods/Materials: Using high resolution copy number analysis of NB tumors we sought for candidate lineage-dependency transcription factors. In vitrofunctional assays were performed upon SOX11knockdown and overexpression. Tumor acceleration was evaluated upon SOX11overexpression in a MYCN-driven zebrafish model. ChIP-seq, ATAC-seq and RNA-sequencing was performed to evaluate the transcriptome and epigenetic landscape, which consequently resulted in the execution of drugging assays for strong candidate targets.Results: We identified recurrent focal gains and amplifications encompassing the SOX11locus and selected this transcription factor as a strong candidate based on (1) its expression in the normal sympatho-adrenal lineage and adrenergic NBs and (2) its control by multiple adrenergic specific distal (super-) enhancers, amongst others. Both in vitroSOX11 knockdown in NB cells and data from the Cancer Dependency Map are indicative for strong dependency of NB cell lines to elevated SOX11expression levels. Furthermore, SOX11 overexpression in a MYCN-driven NB zebrafish model showed accelerated tumor formation. ChIP-sequencing revealed SOX11 controlled transcription of multiple components of major epigenetic modulating protein complexes implicated in chromatin remodeling and enhancer activation (SWI/SNF), chromatin modification (PRC1 and PRC2), DNA methylation as well as several pioneer transcription factors including MYB. Furthermore, ATAC-sequencing indicated SOX11 controlled chromatin opening, predominantly affecting distal enhancers 71marked by SMARCC1 and MYB binding motifs. In addition to the strong co-regulation of MYBand SOX11, SOX11high expressing NB cells showed increased sensitivity for peptidomimetic blockade of MYB.Summary/Conclusions: Our data suggest a key role for SOX11 in the activation of multiple epigenetic modulators in NB leading to an impact on maintenance of adrenergic NB chromatin accessibility and cell identity and contributing to the proliferative MYCNdriven NB phenotype.
Boek: Advances in Neuroblastoma Research (ANR 2021), Abstracts
Aantal pagina's: 1
Jaar van publicatie:2021