Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease

Author:

Araki Takako12ORCID,Tone Yukiko3,Yamamoto Masaaki1,Kameda Hiraku1,Ben-Shlomo Anat1ORCID,Yamada Shozo4,Takeshita Akira4,Yamamoto Masato5ORCID,Kawakami Yasuhiko67ORCID,Tone Masahide3,Melmed Shlomo1ORCID

Affiliation:

1. Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA

2. Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA

3. Pacific Heart, Lung, & Blood Institute, Los Angeles, California, USA

4. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan

5. Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA

6. Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA

7. Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA

Abstract

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.

Funder

National Institutes of Health

University of Minnesota

Publisher

The Endocrine Society

Subject

Biochemistry, medical,Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

Reference40 articles.

1. Pituitary-tumor endocrinopathies;Melmed;N Engl J Med.,2020

2. Stress and disorders of the stress system;Chrousos;Nat Rev Endocrinol.,2009

3. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline;Nieman;J Clin Endocrinol Metab.,2015

4. Silent corticotroph adenomas;Ben-Shlomo;Pituitary.,2018

5. Pituitary tumours: the sst/D2 receptors as molecular targets;Hofland;Mol Cell Endocrinol.,2010

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