Cancer Biology

Promoting Metastasis Through Repression

Science's STKE  15 Oct 2002:
Vol. 2002, Issue 154, pp. tw370-TW370
DOI: 10.1126/stke.2002.154.tw370

The work of Varambally et al. suggests a new model for tumor progression from benign to metastatic (see Zetter and Banyard). The expression of the polycomb group protein enhancer of zeste homolog 2 (EZH2) gene was found to be increased in gene microarray analysis of prostate samples ranging from benign prostate tumors, clinically localized prostate cancer, and metastatic prostate cancer. In addition, metastatic tumors exhibited an increase in the expression of only 55 genes and a decrease in 480 genes. Polycomb group proteins, first identified in Drosophila as part of the regulatory complexes that control homeotic gene expression, are generally considered to be repressors of transcription. Analysis of tissues from prostate tumor samples confirmed that metastatic tumors expressed the greatest amounts of EZH2, whereas benign samples had the lowest amounts. Suppression of EZH2 expression with interfering RNAs led to inhibition of cell proliferation in transformed prostate cell lines. Overexpression of EZH2 led to repression of a large complement of genes and required the SET domain of EZH2 and histone deacetylase activity (presumably provided through interaction of EZH2 with histone deacetylase 2). These results suggest that instead of tumor progression through a series of accumulated mutations, loss of function of a single tumor suppressor may globally affect the expression of multiple genes leading to a rapid progression to a metastatic phenotype.

S. Varambally, S. N. Dhanasekaran, M. Zhou, T. R. Barrette, C. Kumar-Sinha, M. G. Sanda, D. Ghosh, K. J. Pienta, R. G. A. B. Sewalt, A. P. Otte, M. A. Rubin, A. M. Chinnaiyan, The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624-629 (2002). [Online Journal]

B. R. Zetter, J. Banyard, The silence of genes. Nature 419, 572-573 (2002). [Online Journal]