Loss of CASZ1 tumor suppressor linked to oncogenic subversion of neuroblastoma core regulatory circuitry

The neural crest lineage regulatory transcription factors (TFs) form a core regulatory circuitry (CRC) in neuroblastoma (NB) to specify a noradrenergic tumor phenotype. Oncogenic subversion of CRC TFs is well documented, but the role of loss of tumor suppressors plays remains unclear. Zinc-finger TF CASZ1 is a chromosome 1p36 (chr1p36) tumor suppressor. Single-cell RNA sequencing data analyses indicate that CASZ1 is highly expressed in developing chromaffin cells coincident with an expression of NB CRC TFs. In NB tumor cells, the CASZ1 tumor suppressor is silenced while CRC components are highly expressed. We find the NB CRC component HAND2 directly represses CASZ1 expression. ChIP-seq and transcriptomic analyses reveal that restoration of CASZ1 upregulates noradrenergic neuronal genes and represses expression of CRC components by remodeling enhancer activity. Our study identifies that the restored CASZ1 forms a negative feedback regulatory circuit with the established NB CRC to induce noradrenergic neuronal differentiation of NB.

Automated summary

The neural crest lineage regulatory transcription factors (TFs) play a crucial role in neuroblastoma (NB) by forming a core regulatory circuitry (CRC) to specify a specific tumor phenotype. This study focuses on the tumor suppressor CASZ1, which is silenced in NB tumor cells while the CRC components are highly expressed. The research findings indicate that the CRC component HAND2 directly represses CASZ1 expression. Restoring CASZ1 function upregulates noradrenergic neuronal genes and represses CRC component expression by remodeling enhancer activity, forming a negative feedback regulatory circuit with the established NB CRC to induce noradrenergic neuronal differentiation.