Targeting SWI/SNF ATPases reduces cell invasiveness and plasticity in core transcription factors-addicted neuroblastoma [ATAC-seq]

Neuroblastoma (NB) comprises mesenchymal (MES) and adrenergic (ADRN) subtypes, and the cell identity is determined by core transcription factors (TFs). However, the binding mechanism of these TFs to DNA and the epigenetic mechanisms governing NB plasticity remain unclear. In this study, we investigated the impact of targeting SWI/SNF ATPases with SMARCA2/4 dual degraders on NB cells. Our results revealed that depletion of SWI/SNF ATPases compacted cis-regulatory elements, diminished enhancer activity, and displaced core TFs (MYCN, HAND2, PHOX2B, and GATA3) from DNA, suppressing transcriptional programs linked to plasticity and invasiveness. These findings underscore the pivotal role of SWI/SNF ATPases in driving NB progression, positioning them as promising therapeutic targets. Overall design: ATAC-seq was performed in IMR32 cells or BE(2)C cells treated with DMSO (as a vehicle control) or ACBI1 for 24 hours, as well as in IMR5 cells transfected with control siRNA (siCtrl) or SMARCA4 siRNA (siSMARCA4) for 48 hours.