Abstract
Enhancer of zeste homolog 2 (EZH2) is often increased in malignant tumors and is involved in metastasis. EZH2 silences gene expression by tri-methylating the lysine 27 residue of histone H3 (H3K27me3). However, the mechanism underlying EZH2 promotion of ovarian cancer metastasis remains elusive. Here, we showed that EZH2 is up-regulated in ovarian cancer and is associated with tumor metastasis and poor survival by mRNA sequencing and microarray results from databases. Tissue microarray and immunohistochemistry results revealed that EZH2 was negatively correlated with the expression of tissue inhibitor of metalloproteinases 2 (TIMP2). EZH2 overexpression inhibited TIMP2 expression and promoted proteolytic activities of matrix metalloproteinases 2 and 9 and vice versa. EZH2 promoted ovarian cancer invasion and migration, which could be largely reversed by TIMP2 down-regulation in vitro and in vivo. Both H3K27me3 inhibition and demethylation could reduce methylation of the TIMP2 promoter and finally reactivate TIMP2 transcription. The presence of EZH2 and H3K27me3 at the TIMP2 promoter was confirmed by chromatin immunoprecipitation. H3K27me3 and DNA methyltransferases at the promoter were significantly increased by EZH2 overexpression. These results suggest that EZH2 inhibits TIMP2 expression via H3K27me3 and DNA methylation, which relieve the repression of MMP and facilitate ovarian cancer invasion and migration.
Highlights
Ovarian cancer is the most lethal gynecological malignancy
Analysis of Enhancer of zeste homolog 2 (EZH2) mRNA expression data from TCGA database and GEO portal revealed that EZH2 was significantly up-regulated in ovarian cancer compared with normal controls (Supplemental Fig. S1a–d) and high EZH2 expression was related to advanced FIGO stage, poor differentiation, and metastasis (Table 1)
The overall survival time in patients with high EZH2 expression was significantly shorter than those with low EZH2 expression (Supplemental Fig. S1e–h). These findings indicated that EZH2 promotes ovarian cancer progression and metastasis
Summary
Ovarian cancer is the most lethal gynecological malignancy. In 2015, it was estimated that 52,100 Chinese women were newly diagnosed with ovarian cancer and approximately 22,500 women died of this disease[1]. The depletion of EZH2 inhibited ovarian cancer progression in vitro and in vivo[10, 11]. High MMP2 and MMP9 expression promotes ovarian cancer cell invasion and is associated with tumor progression and poor survival in ovarian cancer patients[15, 16]. W. et al delivered ectopic TIMP2 to the mouse abdominal cavity using conditionally replicating adenovirus expressing TIMP2 in the mouse model This upregulation of TIMP2 delayed tumor growth and significantly increased survival[20], indicating that TIMP regulation may have applications in cancer treatment. Bioinformatics analysis of RNA sequencing microarray data confirmed the high EZH2 expression in ovarian cancer and its correlation with metastasis and poor patient survival. The contribution of TIMP2 to the functions of EZH2 was assessed in vivo, and we demonstrated that the epigenetic modifications on the TIMP2 promoter are mediated by EZH2, inhibiting TIMP2 expression
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