lnc-MAP3K13-7:1 Inhibits Ovarian GC Proliferation in PCOS via DNMT1 Downregulation-Mediated CDKN1A Promoter Hypomethylation

Mol Ther. 2021 Mar 3;29(3):1279-1293. doi: 10.1016/j.ymthe.2020.11.018. Epub 2020 Nov 17.

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.

Keywords: DNA methylation; DNMT1; PCOS; epigenetics; granulosa cell proliferation; lncRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Biomarkers / metabolism
  • Cell Cycle
  • Cell Movement
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
  • DNA Methylation*
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation
  • Gene Silencing
  • Granulosa Cells / metabolism
  • Granulosa Cells / pathology*
  • Humans
  • MAP Kinase Kinase Kinases / genetics
  • Ovary / metabolism
  • Ovary / pathology*
  • Polycystic Ovary Syndrome / genetics
  • Polycystic Ovary Syndrome / metabolism
  • Polycystic Ovary Syndrome / pathology*
  • Prognosis
  • Promoter Regions, Genetic
  • RNA, Long Noncoding / genetics*
  • Tumor Cells, Cultured
  • Ubiquitination

Substances

  • Biomarkers
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • RNA, Long Noncoding
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNMT1 protein, human
  • MAP Kinase Kinase Kinases
  • MAP3K13 protein, human