An integrated RNA-Seq and network study reveals that valproate inhibited progesterone production in human granulosa cells.
Cell Line, Tumor
Cell Survival
Cholesterol Side-Chain Cleavage Enzyme
/ metabolism
Female
Gene Expression Profiling
Granulosa Cells
/ drug effects
Humans
Ovary
/ drug effects
Phosphoproteins
/ metabolism
Progesterone
/ metabolism
RNA-Seq
Receptors, Calcitriol
/ metabolism
Steroids
/ metabolism
Transcriptome
Up-Regulation
Valproic Acid
/ pharmacology
Vitamin D Deficiency
/ metabolism
Epilepsy
Granulosa cell
Polycystic ovary syndrome
RNA-seq
Steroidogenesis
Valproate
Journal
The Journal of steroid biochemistry and molecular biology
ISSN: 1879-1220
Titre abrégé: J Steroid Biochem Mol Biol
Pays: England
ID NLM: 9015483
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
15
06
2021
revised:
10
08
2021
accepted:
29
08
2021
pubmed:
7
9
2021
medline:
15
12
2021
entrez:
6
9
2021
Statut:
ppublish
Résumé
Valproate (VPA) is an antiepileptic drug (AEDs) with an ideal effect against epilepsy as well as other neuropsychiatric diseases. There is considerable evidence that women taking VPA are prone to reproductive endocrine disorders. However, few studies have been published about VPA effects on human ovarian granulosa cells. By treating human ovarian granulosa cell line KGN with VPA, the cell viability and progesterone production function were evaluated. RNA-sequencing was applied to uncover the global gene expression upon VPA treatment. We revealed that VPA dose-dependently repressed the viability of KGN. VPA treatment at 600 μM inhibited the progesterone production. The mRNA and protein expression of CYP11A1 and STAR, two key enzymes in the biosynthesis of progesterone, were both suppressed. Gene set enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis of the transcriptome revealed classical functions of VPA as a neuromodulator and regulator of histone acetylation modifications. In addition to this, VPA commonly affected many steroid metabolism related genes in follicle cells, such as promoting the expression of vitamin D receptor (VDR). Our findings suggest that VPA caused steroids metabolism pathways disturbance related with ovarian function and inhibited progesterone biosynthesis by inhibiting the expression of steroidogenesis genes. Our research may provide theoretical basis for the better use of VPA and the possible ways to counteract its side effects.
Sections du résumé
BACKGROUND
Valproate (VPA) is an antiepileptic drug (AEDs) with an ideal effect against epilepsy as well as other neuropsychiatric diseases. There is considerable evidence that women taking VPA are prone to reproductive endocrine disorders. However, few studies have been published about VPA effects on human ovarian granulosa cells.
METHODS
By treating human ovarian granulosa cell line KGN with VPA, the cell viability and progesterone production function were evaluated. RNA-sequencing was applied to uncover the global gene expression upon VPA treatment.
RESULTS
We revealed that VPA dose-dependently repressed the viability of KGN. VPA treatment at 600 μM inhibited the progesterone production. The mRNA and protein expression of CYP11A1 and STAR, two key enzymes in the biosynthesis of progesterone, were both suppressed. Gene set enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis of the transcriptome revealed classical functions of VPA as a neuromodulator and regulator of histone acetylation modifications. In addition to this, VPA commonly affected many steroid metabolism related genes in follicle cells, such as promoting the expression of vitamin D receptor (VDR).
CONCLUSION
Our findings suggest that VPA caused steroids metabolism pathways disturbance related with ovarian function and inhibited progesterone biosynthesis by inhibiting the expression of steroidogenesis genes. Our research may provide theoretical basis for the better use of VPA and the possible ways to counteract its side effects.
Identifiants
pubmed: 34487832
pii: S0960-0760(21)00184-9
doi: 10.1016/j.jsbmb.2021.105991
pii:
doi:
Substances chimiques
Phosphoproteins
0
Receptors, Calcitriol
0
Steroids
0
steroidogenic acute regulatory protein
0
Progesterone
4G7DS2Q64Y
Valproic Acid
614OI1Z5WI
Cholesterol Side-Chain Cleavage Enzyme
EC 1.14.15.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
105991Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.