# PP2A activation targets MYCN in neuroblastoma

## TL;DR

This study shows that activating PP2A can reduce MYCN levels in neuroblastoma, potentially offering a new treatment for high-risk cases.

## Contribution

The novel finding is that PP2A activation directly targets MYCN, a key driver in high-risk neuroblastoma, through epigenetic and transcriptional mechanisms.

## Key findings

- PP2A activators reduce MYCN mRNA and protein expression in neuroblastoma cells.
- PP2A activation decreases H3K27ac at the MYCN promoter and affects RNA Pol II and BRD4 activity.
- Treatment with PP2A activators reduces tumor growth in animal models of neuroblastoma.

## Abstract

Neuroblastoma (NBL) is the most common extracranial solid tumor of childhood, accounting for 7-10% of all children cancers, but leading to 15% of childhood cancer related deaths. Children with high-risk neuroblastoma (HR-NBL) lack effective treatments that achieve durable outcomes. While multiple factors stratify NBL patients into the high- risk category, MYCN amplification is a crucial determinant for that group. Thus far, efforts towards directly targeting MYCN have proven unsuccessful. Serine/threonine protein phosphatase 2 A (PP2A) functions as a tumor suppressor across cancers through its epigenetic effects, and its activity and tumor suppressor function are inhibited in NBL. We hypothesized that MYCN may be a target for PP2A, and that reactivation of PP2A may have a tumor suppressive effect on NBL. We employed studies to document the phenotypic, epigenetic, and in vivo effects of pharmacologic PP2A activation. Novel PP2A activators, ATUX-1215 or ATUX-5800, reduced MYCN mRNA abundance and MYCN phosphorylation and protein expression. PP2A activation decreased the acetylation of H3K27 (H3K27ac) as well as the enrichment of H3K27ac at the MYCN promoter. ATUX-1215 and ATUX-5800 treatment led to hypophosphorylation of RNA Pol II carboxy-terminal domain (CTD) and BRD4, transcriptional and epigenetic regulators respectively, coinciding with decreased MYCN expression and gene regulator acetylation. Tumor growth decreased in animals treated with ATUX-1215, and analysis of tumor specimens confirmed decreased MYCN expression. We conclude that pharmacologic PP2A reactivation may be a relevant therapeutic component in NBL treatment through its targeting of MYCN.