title: Identification of Polycomb Group Protein EZH2-Mediated DNA Mismatch Repair Gene MSH2 in Human Uterine Fibroids.
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 of MutS 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, deregulates MSH2 in UFs. The RNA expression analysis demonstrated the deregulation of MSH2 expression in UF tissues in comparison to its adjacent myometrium. Notably, protein levels of MSH2 were 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 in MSH2 expression (P < .05). Overexpression of EZH2 using an adenoviral vector approach significantly downregulated the expression of MSH2 (P < .05). Chromatin immunoprecipitation assay demonstrated that enrichment of H3K27me3 in promoter regions of MSH2 was 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 gene MSH2, through epigenetic mark H3K27me3. MSH2 may be considered as a marker for early detection of UFs.
authors.affiliation: Division of Translational Research, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, USA qyang@gru.edu.
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Division of Translational Research, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Laknaur
authors.affiliation: Division of Translational Research, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Lelyand
authors.initials: L
authors.lastname: Elam
authors.affiliation: Clinical Microbiology Division, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Nahed
authors.initials: N
authors.lastname: Ismail
authors.affiliation: Division of Translational Research, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Larisa
authors.initials: L
authors.lastname: Gavrilova-Jordan
authors.affiliation: Division of Translational Research, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lue
authors.affiliation: Division of Translational Research, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Diamond
authors.affiliation: Division of Translational Research, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Ayman
authors.initials: A
authors.lastname: Al-Hendy
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053843:DNA Mismatch Repair; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000235:genetics*; D006801:Humans; D007889:Leiomyoma / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009215:Myometrium / Q000378:metabolism; D014594:Uterine Neoplasms / Q000235:genetics*
chemical_list: D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: DNA mismatch repair; EZH2; H3K27me3; MSH2; fibroid; uterine fibroid