PP2A activation targets MYCN in neuroblastoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Neuroblastoma (NBL) is a common childhood cancer with poor outcomes for high-risk patients (HR-NBL).
• MYCN amplification is a key driver in HR-NBL, but direct targeting has been unsuccessful.
• Serine/threonine protein phosphatase 2A (PP2A) acts as a tumor suppressor but is inhibited in NBL.

Purpose of the Study:

• To investigate if MYCN is a target of PP2A and if PP2A reactivation has tumor-suppressive effects in NBL.
• To evaluate the phenotypic, epigenetic, and in vivo effects of pharmacologic PP2A activation.

Main Methods:

• Utilized novel PP2A activators (ATUX-1215, ATUX-5800) in NBL models.
• Assessed effects on MYCN mRNA, phosphorylation, and protein levels.
• Analyzed epigenetic changes including H3K27ac at the MYCN promoter and RNA Pol II CTD/BRD4 phosphorylation.

Main Results:

• PP2A activators significantly reduced MYCN mRNA and protein expression and MYCN phosphorylation.
• Activation of PP2A decreased H3K27ac enrichment at the MYCN promoter and led to hypophosphorylation of RNA Pol II CTD and BRD4.
• Pharmacologic PP2A activation inhibited tumor growth in vivo, with decreased MYCN expression confirmed in tumor specimens.

Conclusions:

• Pharmacologic reactivation of PP2A effectively targets MYCN in NBL.
• PP2A activation demonstrates significant tumor suppressive effects in NBL models.
• Targeting PP2A represents a promising therapeutic strategy for high-risk neuroblastoma.