O-GlcNAcylation Is Essential for Rapid Pomc Expression and Cell Proliferation in Corticotropic Tumor Cells

Abstract

Pituitary adenomas have a staggering 16.7% lifetime prevalence and can be devastating in many patients because of profound endocrine and neurologic dysfunction. To date, no clear genomic or epigenomic markers correlate with their onset or severity. Herein, we investigate the impact of the O-GlcNAc posttranslational modification in their etiology. Found in more than 7000 human proteins to date, O-GlcNAcylation dynamically regulates proteins in critical signaling pathways, and its deregulation is involved in cancer progression and endocrine diseases such as diabetes. In this study, we demonstrated that O-GlcNAc enzymes were upregulated, particularly in aggressive adrenocorticotropin (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 showed that the endocrine function of pituitary adenoma is also dependent on O-GlcNAcylation. In corticotropic tumors, hypersecretion of the proopiomelanocortin (POMC)-derived hormone ACTH leads to Cushing disease, materialized by severe endocrine disruption and increased mortality. We demonstrated that Pomc messenger RNA is stabilized in an O-GlcNAc-dependent manner in response to corticotrophin-releasing hormone (CRH). By affecting 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.

The diverging role of O-GlcNAc Transferase in corticotroph and somatotroph adenomas

“…OGT was shown to repress the recruitment of the glucocorticoid receptor to the Pomc promoter in the mouse pituitary corticotroph cell line AT-t20 [37]. In the same cell line, we have shown that O-GlcNAcylation directly impacts Pomc stability [15]. Using RNA sequencing, we demonstrate in the present article that OGT also correlates with genes involved in RNA splicing mechanisms in functioning corticotroph PAs.…”

“…Interestingly, in NFPAs, OGT correlates with tumor size. Furthermore, ACTH-secreting corticotroph adenomas show a strong correlation with RNA splicing processes, which is a molecular mechanism that we previously highlighted that regulate ACTH processing via O-GlcNAcylation [15]. These new insights may be critical to understanding -and ultimately intervening upon -the mechanisms that promote PAs hyperproliferation and hypersecretion.…”

“…Interestingly, both ACTH and TSH secretion are positively in uenced by hyperglycemia, which also increases O-GlcNAcylation through OGT activity. Thus, it is possible that TSH possesses a similar physiological regulation of secretion dependent on O-GlcNAcylation and OGT level, as demonstrated for ACTH [15,37]. Thus, we can also imagine that having low OGT levels can lead to the inability to answer glucose stimulus and decreased secretion, which is the signature of silent, non-functioning tumors.…”

“…We have previously explored the role of O-GlcNAcylation in vitro, using the murine corticotroph adenoma cell line AtT-20. We demonstrated that O-GlcNAcylation is essential for rapid Pomc expression and AtT-20 cell proliferation [15]. By affecting Pomc mRNA splicing and stability, O-GlcNAcylation contributes to this new mechanism of fast hormonal response in corticotropes.…”

O-GlcNAcylation and Its Role in Cancer-Associated Inflammation

“…Imbalanced levels of O-GlcNAcylation have been found in different kinds of cancers and contributing to various hallmarks of cancers such as tumor growth, metastasis, angiogenesis, cancer stem-like potential and metabolic reprogramming. Recent studies have identified O-GlcNAcylation is essential for the proliferation of corticotropic tumor cells (5). Increased O-GlcNAcylation together with mTOR pathways activation cooperate to increase Fatty acid synthase (FASN) expression to promote tumorigenesis of hepatic tumors (6).…”