What it is
The authors built paired datasets of human pituitary adenomas that cause Cushing's disease and en-route margin tissue from adult human pituitary glands, and profiled their chromatin accessibility, DNA methylation, transcriptome, proteome and phosphoproteome. The adenomas showed epigenetic reactivation of a neurodevelopmental phosphoprotein program normally lost in the pituitary after birth, and overexpressed PPP1R17, an endogenous inhibitor of the phosphatase PP2A. Overexpressing PPP1R17 in normal mouse pituitary cells recapitulated the adenoma phenotype, and the resulting hyperproliferation was reversed, in a PP2A-dependent manner, by the FDA-approved small molecule fingolimod, both in vitro and in vivo.
Why it matters
Pituitary adenomas make up as much as 20% of primary brain tumors, yet somatic mutations are found in only 15% of them, and epigenomic dysregulation had been proposed as a tumorigenic mechanism in the adenomas that cause Cushing's disease. The authors highlight an imbalance between kinases and phosphatases as a targetable mechanism in the disease.
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Filed underPituitary Gland Disorders and Treatments, Glioma Diagnosis and Treatment, Growth Hormone and Insulin-like Growth Factors