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.

miR-137 is a tumor suppressor in endometrial cancer and is repressed by DNA hypermethylation

“…22, 23 Upregulation of EZH2 suppressed MSH2 expression. 24 Those findings suggest that miR-137 methylation associates indirectly associated with MSI status. Functional analysis suggested that miR-137 acts as a tumor suppressor by inhibiting cell proliferation and targeting EZH2 and LSD1 proteins to prevent endometrial cancer.…”

Benign metastasizing leiomyoma presenting with miliary pattern and fatal outcome: Case report with molecular analysis & review of the literature

“…NGS also identified six variants of uncertain significance (VOUS) that were present in both tumors, some of which were reported to be associated with uterine leiomyomata. Of the VOUS that were present in both the uterine and lung tumors, upregulation of MSH2 gene expression, may be considered as a marker for early detection of uterine fibroids [25]. However, without a matched normal, to rule out germline variants, the significance of these variants is not clear.…”

Telomerase reverse transcriptase (TERT) ‐ enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma

“…EZH2 regulates MSH2 through H3K27me3 (Yang et al . ), and a decrease in MSH2 level was observed upon siRNA‐mediated EZH2 knockdown (Fig. f and Figure S6e).…”