SAT-008 - Reducing ACTH Secretion in Corticotroph Adenomas by Controlling O-GlcNAc Levels

Objective: Pituitary adenomas disrupt endocrine homeostasis through dysregulated hormone secretion, contributing to significant clinical morbidity. Corticotroph adenomas are characterized by overexpression of pro-opiomelanocortin (POMC) and excess secretion of its cleavage product, adrenocorticotropic hormone (ACTH), which is associated with increased cardiovascular risk. O-linked β-N-acetylglucosamine (O-GlcNAc) modification is a dynamic post-translational process that regulates gene expression in response to cellular metabolic status, yet its role in pituitary hormone regulation remains poorly defined. This study investigates the contribution of O-GlcNAcylation to POMC expression and ACTH secretion in corticotroph adenoma models.

Methods: We employed a combination of in vitro and ex vivo systems, including the murine corticotroph adenoma cell line AtT20 and primary mouse and human pituitary tissue cultures. Pharmacologic and molecular approaches were used to modulate O-GlcNAc cycling and assess downstream effects on Pomc transcription, mRNA stability, and ACTH secretion.

Results: O-GlcNAcylation was found to be a critical regulator of Pomc mRNA expression, increasing transcript levels in response to corticotropin-releasing hormone stimulation and promoting mRNA stability. Bioinformatic analyses implicates O-GlcNAc-modified RNA-binding and processing proteins in reducing Pomc transcript turnover. While global O-GlcNAc levels were not significantly altered by extracellular glucose availability, inhibition of O-GlcNAc cycling enzymes led to a marked reduction in ACTH secretion.

Conclusions: These findings identify O-GlcNAcylation as a key regulatory mechanism governing POMC gene expression and ACTH secretion in corticotroph adenomas. Targeting O-GlcNAc-dependent pathways may represent a novel therapeutic strategy for mitigating ACTH-driven morbidity in pituitary disease.

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