Aberrant G protein-receptor expression is associated with DNA methylation in aldosterone-producing adenoma

Kiyotaka Itcho; Kenji Oki; Kazuhiro Kobuke; Yoko Yoshii; Haruya Ohno; Masayasu Yoneda; Noboru Hattori

doi:10.1016/j.mce.2017.08.019

Aberrant G protein-receptor expression is associated with DNA methylation in aldosterone-producing adenoma

Mol Cell Endocrinol. 2018 Feb 5:461:100-104. doi: 10.1016/j.mce.2017.08.019. Epub 2017 Sep 7.

Authors

Kiyotaka Itcho¹, Kenji Oki², Kazuhiro Kobuke¹, Yoko Yoshii¹, Haruya Ohno¹, Masayasu Yoneda¹, Noboru Hattori¹

Affiliations

¹ Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
² Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address: kenjioki@hiroshima-u.ac.jp.

PMID: 28870781
DOI: 10.1016/j.mce.2017.08.019

Abstract

This study aimed to evaluate the methylation levels of G protein-coupled receptor (GPCR) related genes and the effects of methylation on mRNA expression levels in aldosterone-producing adenoma (APA). DNA methylation array and transcriptome analysis were applied in non-functioning adrenocortical adenoma (NFA) and APA. We investigated 192 GPCR-related genes and found hypo-methylation in the promoter region of 66 of these genes in APA. An integration study between microarray and methylation analysis revealed that HTR4, MC2R, TACR1, GRM3, and PTGER1 showed hypo-methylation and up-regulation of mRNA in APA. qPCR analysis showed that HTR4 and PTGER1 expression was 9.3-fold and 6.6-fold higher in APAs than in NFAs, respectively, whereas expression of the other genes was not different between the groups. Methylation of HTR4 and PTGER1 at positions -229 and -666 from the transcription start site, respectively, showed a significant inverse correlation with their mRNA levels. Methylation levels were not associated with KCNJ5 or ATP1A1 mutations in human adrenal samples. We demonstrated an increased incidence of CpG island demethylation of GPCR-related gene in APA. The expression of two receptors, HTR4 and PTGER1, showed a strong association with DNA methylation.

Keywords: Aldosterone-producing adenoma; DNA methylation; G protein-coupled receptor; Prostaglandin E receptor; Serotonin receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoma / genetics*
Aldosterone / biosynthesis*
DNA Methylation / genetics*
Gene Expression Regulation, Neoplastic
Genes, Neoplasm
Genotype
Humans
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, G-Protein-Coupled / metabolism*

Substances

RNA, Messenger
Receptors, G-Protein-Coupled
Aldosterone