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O-GlcNAcylation Is Essential for Rapid Pomc Expression and Cell Proliferation in Corticotropic Tumor Cells. Endocrinology 2021 12 01;162(12)

Date

08/22/2021

Pubmed ID

34418053

Pubmed Central ID

PMC8482966

DOI

10.1210/endocr/bqab178

Scopus ID

2-s2.0-85117209862   1 Citation

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.

Author List

Massman LJ, Pereckas M, Zwagerman NT, Olivier-Van Stichelen S

Authors

Stephanie Olivier-Van Stichelen PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin
Nathan Zwagerman MD Associate Professor in the Neurosurgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

ACTH-Secreting Pituitary Adenoma
Acetylglucosamine
Adenoma
Aged
Cell Proliferation
Cells, Cultured
Gene Expression Regulation, Neoplastic
Humans
Male
N-Acetylglucosaminyltransferases
Pro-Opiomelanocortin
Promoter Regions, Genetic
Protein Processing, Post-Translational
RNA Stability