Epigenetic reactivation of a neurodevelopmental phosphoprotein program in pituitary adenomas

Abstract Background: The protein kinase-phosphatase equilibrium is essential for eukaryotic development and homeostasis, but its epigenomic dysregulation in human tumors remains unexplored.Objectives/Methods: We employed an omics-based approach to elucidate the molecular mechanisms of pituitary adenomas, which comprise 20% of primary brain tumors. We created paired datasets of human pituitary adenomas and adjacent normal human pituitary glands, assaying chromatin accessibility, DNA methylation, transcriptomic, proteomic, and phospho-proteomic landscapes.Results: Adrenocorticotropin secreting adenoma cells reactivated a postnatally lost neurodevelopmental phosphoprotein program and overexpressed PPP1R17, an inhibitor of tumor suppressor PP2A. PPP1R17 overexpression in murine pituitary cells mirrored the adenoma phenotype, which was reversible with an FDA-approved PP2A agonist.Conclusions: Our study identified the epigenetic reactivation of a neurodevelopmental phosphoprotein program as a potential therapeutic target for human tumors.