Identification of Polycomb Group Protein EZH2-Mediated DNA Mismatch Repair Gene MSH2 in Human Uterine Fibroids

Qiwei Yang, Archana Laknaur, Lelyand Elam, Nahed Ismail, Larisa Gavrilova-Jordan, John Lue, Michael P. Diamond, Ayman Al-Hendy

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Uterine fibroids (UFs) are benign smooth muscle neoplasms affecting up to 70% of reproductive age women. Treatment of symptomatic UFs places a significant economic burden on the US health-care system. Several specific genetic abnormalities have been described as etiologic factors of UFs, suggesting that a low DNA damage repair capacity may be involved in the formation of UF. In this study, we used human fibroid and adjacent myometrial tissues, as well as an in vitro cell culture model, to evaluate the expression ofMutS homolog 2(MSH2), which encodes a protein belongs to the mismatch repair system. In addition, we deciphered the mechanism by which polycomb repressive complex 2 protein, EZH2, deregulatesMSH2in UFs. The RNA expression analysis demonstrated the deregulation ofMSH2expression in UF tissues in comparison to its adjacent myometrium. Notably, protein levels ofMSH2were upregulated in 90% of fibroid tissues (9 of 10) as compared to matched adjacent myometrial tissues. Human fibroid primary cells treated with 3-deazaneplanocin A (DZNep), chemical inhibitor of EZH2, exhibited a significant increase inMSH2expression (P< .05). Overexpression ofEZH2using an adenoviral vector approach significantly downregulated the expression ofMSH2(P< .05). Chromatin immunoprecipitation assay demonstrated that enrichment of H3K27me3 in promoter regions ofMSH2was significantly decreased in DZNep-treated fibroid cells as compared to vehicle control. These data suggest that EZH2-H3K27me3 regulatory mechanism dynamically changes the expression levels of DNA mismatch repair geneMSH2,through epigenetic mark H3K27me3. MSH2 may be considered as a marker for early detection of UFs.

Original languageEnglish (US)
Pages (from-to)1314-1325
Number of pages12
JournalReproductive Sciences
Volume23
Issue number10
DOIs
StatePublished - Mar 31 2016

Keywords

  • DNA mismatch repair
  • EZH2
  • fibroid
  • H3K27me3
  • MSH2
  • uterine fibroid

ASJC Scopus subject areas

  • Obstetrics and Gynecology

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