Document Type

Journal Article

Publication Date

1-17-2012

Journal

PLoS ONE

Volume

Volume 7, Issue 1

Inclusive Pages

Article number e30393

Keywords

DNA-Binding Proteins--genetics; Gene Expression Regulation; Neoplastic; Matrix Metalloproteinase 9--genetics; Tissue Inhibitor of Metalloproteinase-2--genetics; Tissue Inhibitor of Metalloproteinase-3--genetics; Transcription Factors--genetics

Abstract

Degradation of the extracellular matrix (ECM), a critical step in cancer metastasis, is determined by the balance between MMPs (matrix metalloproteinases) and their inhibitors TIMPs (tissue inhibitors of metalloproteinases). In cancer cells, this balance is shifted towards MMPs, promoting ECM degradation. Here, we show that EZH2 plays an active role in this process by repressing the expression of TIMP2 and TIMP3 in prostate cancer cells. The TIMPgenes are derepressed by knockdown of EZH2 expression in human prostate cancer cells but repressed by overexpression of EZH2 in benign human prostate epithelial cells. EZH2 catalyzes H3K27 trimethylation and subsequent DNA methylation of the TIMP gene promoters. Overexpression of EZH2 confers an invasive phenotype on benign prostate epithelial cells; however, this phenotype is suppressed by cooverexpression of TIMP3. EZH2 knockdown markedly reduces the proteolytic activity of MMP-9, thereby decreasing the invasive activity of prostate cancer cells. These results suggest that the transcriptional repression of the TIMPgenes by EZH2 may be a major mechanism to shift the MMPs/TIMPs balance in favor of MMP activity and thus to promote ECM degradation and subsequent invasion of prostate cancer cells.

Comments

Reproduced with permission of PLoS ONE.

Creative Commons License


This work is licensed under a Creative Commons Attribution 3.0 License.

Peer Reviewed

1

Open Access

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