TY - JOUR
T1 - Identification of Polycomb Group Protein EZH2-Mediated DNA Mismatch Repair Gene MSH2 in Human Uterine Fibroids
AU - Yang, Qiwei
AU - Laknaur, Archana
AU - Elam, Lelyand
AU - Ismail, Nahed
AU - Gavrilova-Jordan, Larisa
AU - Lue, John
AU - Diamond, Michael P.
AU - Al-Hendy, Ayman
N1 - © The Author(s) 2016.
PY - 2016/3/31
Y1 - 2016/3/31
N2 - 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.
AB - 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.
KW - DNA mismatch repair
KW - EZH2
KW - fibroid
KW - H3K27me3
KW - MSH2
KW - uterine fibroid
UR - http://www.scopus.com/inward/record.url?scp=84987859201&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84987859201&partnerID=8YFLogxK
U2 - 10.1177/1933719116638186
DO - 10.1177/1933719116638186
M3 - Article
C2 - 27036951
SN - 1933-7191
VL - 23
SP - 1314
EP - 1325
JO - Reproductive Sciences
JF - Reproductive Sciences
IS - 10
ER -