O-GlcNAcylation is essential for rapid Pomc expression and cell proliferation in corticotropic tumor cells (Supplementary Materials, Figures and Tables)

Pituitary 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.