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 TIMP genes 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 TIMP genes 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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Adenosine / analogs & derivatives
-
Adenosine / pharmacology
-
Blotting, Western
-
Cell Line, Tumor
-
Cell Movement
-
DNA-Binding Proteins / genetics*
-
DNA-Binding Proteins / metabolism
-
Down-Regulation / drug effects
-
Enhancer of Zeste Homolog 2 Protein
-
Gene Expression Regulation, Neoplastic*
-
Humans
-
Immunohistochemistry
-
Male
-
Matrix Metalloproteinase 9 / genetics*
-
Neoplasm Invasiveness
-
Neoplasm Metastasis
-
Polycomb Repressive Complex 2
-
Prostatic Neoplasms / genetics
-
Prostatic Neoplasms / metabolism
-
Prostatic Neoplasms / pathology
-
RNA Interference
-
Reverse Transcriptase Polymerase Chain Reaction
-
Tissue Inhibitor of Metalloproteinase-2 / genetics*
-
Tissue Inhibitor of Metalloproteinase-2 / metabolism
-
Tissue Inhibitor of Metalloproteinase-3 / genetics*
-
Tissue Inhibitor of Metalloproteinase-3 / metabolism
-
Transcription Factors / genetics*
-
Transcription Factors / metabolism
Substances
-
DNA-Binding Proteins
-
TIMP2 protein, human
-
TIMP3 protein, human
-
Tissue Inhibitor of Metalloproteinase-3
-
Transcription Factors
-
Tissue Inhibitor of Metalloproteinase-2
-
3-deazaneplanocin
-
EZH2 protein, human
-
Enhancer of Zeste Homolog 2 Protein
-
Polycomb Repressive Complex 2
-
Matrix Metalloproteinase 9
-
Adenosine