Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease

Takako Araki, Yukiko Tone, Masaaki Yamamoto, Hiraku Kameda, Anat Ben-Shlomo, Shozo Yamada, Akira Takeshita, Masato Yamamoto, Yasuhiko Kawakami, Masahide Tone, Shlomo Melmed

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Context: Mechanisms underlying pituitary corticotroph adenoma adrenocorticotropin (ACTH) production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. Objective: We characterized the 5′ ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. Methods: We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent corticotroph adenomas (SCAs) that immunostain for but do not secrete ACTH. Results: We identified a novel regulatory region located near the intron 2/exon 3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCAs, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the ubiquitin-specific protease 8 (USP8) mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing disease. Conclusion: We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.

Original languageEnglish (US)
Pages (from-to)E3346-E3363
JournalJournal of Clinical Endocrinology and Metabolism
Volume106
Issue number9
DOIs
StatePublished - Aug 18 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.

Keywords

  • ACTH
  • Cushing disease
  • POMC
  • pituitary adenoma

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