Cancer Biology
Biomarkers in general can be useful in the clinic regardless of their role in cancer development. It is likely, however, that the genomic approaches we employ in the Cancer Biology Laboratory may identify candidate regulatory genes that may be involved in the biology of neoplastic progression. This component of the lab focuses on characterizing the function(s) of these candidate genes in cancer development.
Characterization of the Polycomb Group Protein EZH2 in prostate cancer progression is a successful example derived from this paradigm. Using DNA microarrays, we identified EZH2 as being up-regulated in hormone-refractory metastatic prostate cancer (Nature, 419:624).
We also observed that EZH2 was elevated in patients with aggressive clinically-localized disease, thereby suggesting an important role for this protein in prostate cancer pathogenesis. In Drosophila, PcG proteins have been shown to maintain gene expression programs during development by negatively regulating target loci, including homeotic genes. The cellular memory (or transcriptional memory) machinery maintains gene expression patterns through cell division. PcG proteins in concert with TrxG (Trithorax) proteins are thought to control transcriptional repression and activation, respectively. Dysregulation of the cell memory machinery can lead to cancer. EZH2 functions in a complex of PcG proteins that includes EED and SUZ12. EZH2 is especially interesting as it has been shown to possess enzymatic activity as a histone H3 methyltransferase.
Based on these observations, we believe it is likely that dysregulated expression of the PcG protein EZH2 promotes the growth of prostate cancer by transcriptional silencing of specific target genes. We are in the process of characterizing these target genes by a combination of transcriptome analyses and chromatin immunoprecipitation analyses. EZH2 mis-expression in prostate cancer may lead to prostate cancer metastasis and growth of metastatic tumors. More recent studies by our group have shown that over-expression of EZH2 in immortalized benign prostate or breast cell lines induces anchorage-independent growth and cell invasion (PNAS 100:11606). We are attempting to delineate the mechanism of EZH2-mediated cell invasion which we postulate is through repression of target genes. In parallel with our in vitro models, we also are developing in vivo models of EZH2 function, including a transgenic mouse model that over-expresses EZH2 in the prostate.
In collaboration with others at the University, we are delving into the structure-function relationship of EZH2 in relation to the PcG complex.
Potentially, this work will lead to the discovery of small molecule inhibitors that target the enzymatic activity of EZH2 that we postulate will be useful in blocking cancer metastasis.
