Although the mechanisms driving pituitary corticotroph adenoma adrenocorticotropin (ACTH) synthesis are unknown, circulating ACTH levels are closely related to adenoma phenotype and clinical consequences. In order to study other regulatory mechanisms of POMC gene transcription and ACTH synthesis, researchers characterised the 5′ ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH. They discovered a new regulatory region in the human POMC gene near the intron 2/exon 3 junction that acts as a second promoter and an enhancer. CREB binds the second promoter and controls its transcriptional activity, according to in vitro studies. The second promoter is heavily methylated in SCAs, partly demethylated in normal pituitary tissue, and completely demethylated in pituitary and ectopic ACTH-secreting tumours. The first promoter, on the other hand, is demethylated in all POMC-expressing cells and is substantially demethylated only in pituitary ACTH-secreting tumours with the ubiquitin-specific protease 8 (USP8) mutation. The patterns of demethylation of the second promoter are related to clinical characteristics of Cushing illness.

In ACTH-secreting pituitary tumours, we discovered a second POMC promoter that is controlled by methylation status. The findings provide fresh insights into the subcellular control of the hypothalamic-pituitary-adrenal axis and suggest that the second POMC promoter might be a therapeutic target for suppressing excess ACTH production.