Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia

Mitsuhiro Kometani, Takashi Yoneda, Masashi Demura, Hiroshi Koide, Koshiro Nishimoto, Kuniaki Mukai, Celso E. Gomez-Sanchez, Tadayuki Akagi, Takashi Yokota, Shin Ichi Horike, Shigehiro Karashima, Isamu Miyamori, Masakazu Yamagishi, Yoshiyu Takeda

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Abstract

Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11β-hydroxylase (CYP11B1), which catalyzes cortisol biosynthesis and is highly homologous to CYP11B2, is unclear. The aims of our study were to determine whether the CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with cortisol-producing adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter.

Original languageEnglish
Article number11205
JournalScientific reports
Volume7
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

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    Kometani, M., Yoneda, T., Demura, M., Koide, H., Nishimoto, K., Mukai, K., Gomez-Sanchez, C. E., Akagi, T., Yokota, T., Horike, S. I., Karashima, S., Miyamori, I., Yamagishi, M., & Takeda, Y. (2017). Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia. Scientific reports, 7(1), [11205]. https://doi.org/10.1038/s41598-017-11435-2