Hypomethylation associated vitamin D receptor expression in ATP1A1 mutant aldosterone-producing adenoma

Nanao, Yuta; Oki, Kenji; Kobuke, Kazuhiro; Itcho, Kiyotaka; Baba, Ryuta; Kodama, Takaya; Otagaki, Yu; Okada, Akira; Yoshii, Yoko; Nagano, Gaku; Ohno, Haruya; Arihiro, Koji; Gómez-Sánchez, Celso E.; Hattori, Noboru; Yoneda, Masayasu

doi:10.1016/j.mce.2022.111613

Cited by 3 publications

(1 citation statement)

References 52 publications

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“…Similarly, pediatric adrenocortical tumors with high VDR promoter methylation had lower VDR mRNA levels and correlated with advanced disease and reduced survival in these patients ( 93 ). Conversely, hypomethylation of VDR promoter in adrenocortical adenoma tissue correlated with more differentiation and aldosterone production from those tumors ( 94 ). Methylation of VDR promoter was shown to be important in acute myeloid leukemia cells and DNA methyltransferase inhibitor 5-aza induced VDR expression ( 95 ).…”

Section: Methylationmentioning

confidence: 99%

PTH, FGF-23, Klotho and Vitamin D as regulators of calcium and phosphorus: Genetics, epigenetics and beyond

Portales‐Castillo

Šimić

2022

Front. Endocrinol.

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The actions of several bone-mineral ion regulators, namely PTH, FGF23, Klotho and 1,25(OH)2 vitamin D (1,25(OH)2D), control calcium and phosphate metabolism, and each of these molecules has additional biological effects related to cell signaling, metabolism and ultimately survival. Therefore, these factors are tightly regulated at various levels – genetic, epigenetic, protein secretion and cleavage. We review the main determinants of mineral homeostasis including well-established genetic and post-translational regulators and bring attention to the epigenetic mechanisms that affect the function of PTH, FGF23/Klotho and 1,25(OH)2D. Clinically relevant epigenetic mechanisms include methylation of cytosine at CpG-rich islands, histone deacetylation and micro-RNA interference. For example, sporadic pseudohypoparathyroidism type 1B (PHP1B), a disease characterized by resistance to PTH actions due to blunted intracellular cAMP signaling at the PTH/PTHrP receptor, is associated with abnormal methylation at the GNAS locus, thereby leading to reduced expression of the stimulatory G protein α-subunit (Gsα). Post-translational regulation is critical for the function of FGF-23 and such modifications include glycosylation and phosphorylation, which regulate the cleavage of FGF-23 and hence the proportion of available FGF-23 that is biologically active. While there is extensive data on how 1,25(OH)2D and the vitamin D receptor (VDR) regulate other genes, much more needs to be learned about their regulation. Reduced VDR expression or VDR mutations are the cause of rickets and are thought to contribute to different disorders. Epigenetic changes, such as increased methylation of the VDR resulting in decreased expression are associated with several cancers and infections. Genetic and epigenetic determinants play crucial roles in the function of mineral factors and their disorders lead to different diseases related to bone and beyond.

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Section: Methylationmentioning

confidence: 99%

PTH, FGF-23, Klotho and Vitamin D as regulators of calcium and phosphorus: Genetics, epigenetics and beyond

Portales‐Castillo

Šimić

2022

Front. Endocrinol.

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Vitamin D receptor activation is a feasible therapeutic target to impair adrenocortical tumorigenesis

Bueno

Marrero-Gutiérrez

Silva

et al. 2022

Molecular and Cellular Endocrinology

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

Kodama

Oki

Otagaki

et al. 2022

Endocrine-Related Cancer

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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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Hypomethylation associated vitamin D receptor expression in ATP1A1 mutant aldosterone-producing adenoma

Cited by 3 publications

References 52 publications

PTH, FGF-23, Klotho and Vitamin D as regulators of calcium and phosphorus: Genetics, epigenetics and beyond

PTH, FGF-23, Klotho and Vitamin D as regulators of calcium and phosphorus: Genetics, epigenetics and beyond

Vitamin D receptor activation is a feasible therapeutic target to impair adrenocortical tumorigenesis

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

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