title: The Polycomb Group Protein EZH2 Impairs DNA Damage Repair Gene Expression in Human Uterine Fibroids.
abstract: Uterine fibroids are benign, smooth muscle tumors that occur in approximately 70%-80% of women by age 50 yr. The cellular and molecular mechanism(s) by which uterine fibroids (UFs) develop are not fully understood. Accumulating evidence demonstrates that several genetic abnormalities, including deletions, rearrangements, translocations, as well as mutations, have been found in UFs. These genetic anomalies suggest that low DNA damage repair capacity may be involved in UF formation. The objective of this study was to determine whether expression levels of DNA damage repair-related genes were altered, and how they were regulated in the pathogenesis of UFs. Expression levels of DNA repair-related genes RAD51 and BRCA1 were deregulated in fibroid tissues as compared to adjacent myometrial tissues. Expression levels of chromatin protein enhancer of zeste homolog 2 (EZH2) were higher in a subset of fibroids as compared to adjacent myometrial tissues by both immunohistochemistry and Western blot analysis. Treatment with an inhibitor of EZH2 markedly increased expression levels of RAD51 and BRCA1 in fibroid cells and inhibited cell proliferation paired with cell cycle arrest. Restoring the expression of RAD51 and BRCA1 by treatment with EZH2 inhibitor was dependent on reducing the enrichment of trimethylation of histone 3 lysine 27 epigenetic mark in their promoter regions. This study reveals the important role of EZH2-regulated DNA damage-repair genes via histone methylation in fibroid biology, and may provide novel therapeutic targets for the medical treatment of women with symptomatic UFs.
authors.affiliation: Division of Translation Research, Department of Obstetrics and Gynecology, Augusta University, Medical College of Georgia, Augusta, Georgia qyang@gru.edu.
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Division of Translation Research, Department of Obstetrics and Gynecology, Augusta University, Medical College of Georgia, Augusta, Georgia.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Nair
authors.affiliation: Division of Translation Research, Department of Obstetrics and Gynecology, Augusta University, Medical College of Georgia, Augusta, Georgia.
authors.forename: Archana
authors.initials: A
authors.lastname: Laknaur
authors.affiliation: Clinical Microbiology Division, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Nahed
authors.initials: N
authors.lastname: Ismail
authors.affiliation: Division of Translation Research, Department of Obstetrics and Gynecology, Augusta University, Medical College of Georgia, Augusta, Georgia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Diamond
authors.affiliation: Division of Translation Research, Department of Obstetrics and Gynecology, Augusta University, Medical College of Georgia, Augusta, Georgia.
authors.forename: Ayman
authors.initials: A
authors.lastname: Al-Hendy
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000502:physiology*; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007889:Leiomyoma / Q000378:metabolism*; D009215:Myometrium / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C495153:RAD51 protein, human; D051135:Rad51 Recombinase
keywords: BRCA1; DNA damage repair; EZH2; H3K27me3; RAD51; fibroid