Phosphoproteomic dysregulation promotes tumor proliferation in Cushing’s disease

Pituitary adenomas constitute up to 20% of primary brain tumors, yet somatic mutations are only found in 15% of pituitary adenomas. Epigenomic dysregulation has been proposed as a tumorigenic mechanism in pituitary adenomas causing Cushing’s disease (CD). We created paired datasets of human CD adenomas and en-route margin adult human pituitary glands, and assayed their chromatin accessibility, DNA methylation, transcriptomic, proteomic, and phospho-proteomic landscapes. In CD adenomas, we found epigenetic reactivation of a neurodevelopmental phosphoprotein program typically lost in the postnatal pituitary gland. CD cells overexpressed PPP1R17 , an endogenous inhibitor of the protein phosphatase PP2A. Mechanistically, PPP1R17 overexpression in normal murine pituitary cells recapitulated the adenoma phenotype, and the resulting hyperproliferation was reversed in a PP2A-dependent manner by fingolimod, an FDA-approved small molecule, both in vitro and in vivo. Our findings highlight kinase-phosphatase imbalance as a targetable mechanism in CD.