O-GlcNAcylation is essential for rapid Pomc expression and cell proliferation in corticotropic tumor cells

Abstract

ABSTRACTPituitary adenomas have a staggering 16.7% lifetime prevalence and can be devastating in many patients due to profound endocrine and neurologic dysfunction. To date, no clear genomic or epigenomic markers correlates with their onset or severity. Herein, we investigate the impact of the O-GlcNAc post-translational modification in their etiology. Found in over 5000 human proteins to date, O-GlcNAcylation dynamically regulates proteins in critical signaling pathways, and its deregulation is involved in cancers progression and endocrine diseases such as diabetes.In this study, we demonstrate that O-GlcNAcylation enzymes were upregulated, particularly in aggressive ACTH-secreting tumors, suggesting a role for O-GlcNAcylation in pituitary adenoma etiology. In addition to the demonstration that O-GlcNAcylation was essential for their proliferation, we show that the endocrine function of pituitary adenoma is also dependent on O-GlcNAcylation. In corticotropic tumors, hyper-secretion of the proopiomelanocortin (POMC)-derived hormone ACTH leads to Cushing’s disease, materialized by severe endocrine disruption and increased mortality. We demonstrate that Pomc mRNA is stabilized in an O-GlcNAc-dependent manner in response to corticotropic-stimulating hormone (CRH). By impacting Pomc mRNA splicing and stability, O-GlcNAcylation contributes to this new mechanism of fast hormonal response in corticotropes. Thus, this study stresses the essential role of O-GlcNAcylation in ACTH-secreting adenomas’ pathophysiology, including cellular proliferation and hypersecretion.