the role of ezh2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cellsezh2的作用在调节基质金属蛋白酶在前列腺癌细胞的活性.pdfVIP

The Role of EZH2 in the Regulation of the Activity of Matrix Metalloproteinases in Prostate Cancer Cells Yong Jae Shin, Jeong-Ho Kim* Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, D.C., United States of America 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. Citation: Shin YJ, Kim J-H (2012) The Role of EZH2 in the Regulation of the Activity of Matrix Metalloproteinases in Prostate Cancer Cells. PLoS ONE 7(1): e30393. doi:10.1371/journal.pone.0030393 Editor: Dean G. Tang, The University of Texas M.D Anderson Cancer Center, United States of America Receive