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lnc-MAP3K13-7:1 Inhibits Ovarian GC Proliferation in PCOS via DNMT1 Downregulation-Mediated CDKN1A Promoter Hypomethylation
- Source :
- Molecular therapy : the journal of the American Society of Gene Therapy. 29(3)
- Publication Year :
- 2020
-
Abstract
- Polycystic ovary syndrome (PCOS) is an endocrine-related disease and global cause of infertility that is associated with abnormal folliculogenesis. Inhibited granulosa cell (GC) proliferation is recognized as a key factor that underlies aberrant follicle maturation. Many epigenetic landscape modifications have been characterized in PCOS patients. However, the epigenetic regulation pathways in follicular dysplasia are not completely understood. In this study, we reported a novel mechanism of DNA hypomethylation induced by long non-coding RNAs (lncRNAs) and its function in cell cycle progression. We observed that lnc-MAP3K13-7:1 was highly expressed in GCs from patients with PCOS, with concomitant global DNA hypomethylation, decreased DNA methyltransferase 1 (DNMT1) expression, and increased cyclin-dependent kinase inhibitor 1A (CDKN1A, p21) expression. In KGN cells, lnc-MAP3K13-7:1 overexpression resulted in cell cycle arrest in the G0/G1 phase, as well as the molecular inhibition and genetic silencing of DNMT1. Mechanistically, lnc-MAP3K13-7:1 inhibited DNMT1 expression by acting as a protein-binding scaffold and inducing ubiquitin-mediated DNMT1 protein degradation. Moreover, DNMT1-dependent CDKN1A promoter hypomethylation increased CDKN1A transcription, resulting in attenuated GC growth. Our work uncovered a novel and essential mechanism through which lnc-MAP3K13-7:1-dependent DNMT1 inhibition regulates CDKN1A/p21 expression and inhibits GC proliferation.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
DNA (Cytosine-5-)-Methyltransferase 1
Granulosa cell
Apoptosis
Protein degradation
Epigenesis, Genetic
03 medical and health sciences
0302 clinical medicine
Cell Movement
Drug Discovery
Genetics
Tumor Cells, Cultured
Humans
Epigenetics
Gene Silencing
Promoter Regions, Genetic
Molecular Biology
Granulosa cell proliferation
030304 developmental biology
Cell Proliferation
Pharmacology
0303 health sciences
Granulosa Cells
Chemistry
Cell Cycle
Ovary
Ubiquitination
DNA Methylation
MAP Kinase Kinase Kinases
Prognosis
Polycystic ovary
Gene Expression Regulation
030220 oncology & carcinogenesis
DNA methylation
Cancer research
DNMT1
Molecular Medicine
Female
RNA, Long Noncoding
Biomarkers
DNA hypomethylation
Polycystic Ovary Syndrome
Subjects
Details
- ISSN :
- 15250024
- Volume :
- 29
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Accession number :
- edsair.doi.dedup.....5226c0151cc06fc43c6dc215ca282d3f