Association of DNA methylation with steroidogenic enzymes in Cushing’s adenoma

in Endocrine-Related Cancer
Authors:
Takaya Kodama Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Kenji Oki Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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https://orcid.org/0000-0002-9225-8193
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Yu Otagaki Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Ryuta Baba Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Akira Okada Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Kiyotaka Itcho Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Kazuhiro Kobuke Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Gaku Nagano Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Haruya Ohno Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Nobuyuki Hinata Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Koji Arihiro Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan

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Celso E Gomez-Sanchez Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center and University of Mississippi Medical Center, Jackson, Mississippi, USA
Department of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA

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Masayasu Yoneda Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Noboru Hattori Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

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Correspondence should be addressed to K Oki: kenjioki@hiroshima-u.ac.jp
DOI:
https://doi.org/10.1530/ERC-22-0115
Volume/Issue:
Volume 29: Issue 8
Article Type:
Research Article
Page Range:
495–502
Online Publication Date:
29 Jun 2022
Copyright:
© Society for Endocrinology 2022
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DNA methylation and demethylation regulate the transcription of genes. DNA methylation-associated gene expression of adrenal steroidogenic enzymes may regulate cortisol production in cortisol-producing adenoma (CPA). We aimed to determine the DNA methylation levels of all genes encoding steroidogenic enzymes involved in CPA. Additionally, the aims were to clarify the DNA methylation-associated gene expression and evaluate the difference of CPA genotype from others using DNA methylation data. Twenty-five adrenal CPA and six nonfunctioning adrenocortical adenoma (NFA) samples were analyzed. RNA sequencing and DNA methylation array were performed. The methylation levels at 118 methylation sites of the genes were investigated, and their methylation and mRNA levels were subsequently integrated. Among all the steroidogenic enzyme genes studied, CYP17A1 gene was mainly found to be hypomethylated in CPA compared to that in NFA, and the Benjamini-Hochberg procedure demonstrated that methylation levels at two sites in the CYP17A1 gene body were statistically significant. PRKACA mutant CPAs predominantly exhibited hypomethylation of CYP17A1 gene compared with the GNAS mutant CPAs. Inverse associations between CYP17A1 methylation in three regions of the gene body and its mRNA levels were observed in the NFAs and CPAs. In applying clustering analysis using CYP17A1 methylation and mRNA levels, CPAs with PRKACA mutation were differentiated from NFAs and CPAs with a GNAS mutation. We demonstrated that CPAs exhibited hypomethylation of the CYP17A1 gene body in CPA, especially in the PRKACA mutant CPAs. Methylation of CYP17A1 gene may influence its transcription levels.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© Society for Endocrinology 2022
Page(s):
8
Received Date:
22 May 2022
Accepted Date:
08 Jun 2022
Print Publication Date:
01 Aug 2022
Online Publication Date:
29 Jun 2022
Keywords:
Cushing’s syndrome; DNA methylation; CYP17A1; PRKACA; gene expression

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