Epigenetic silencing in cancer cells is mediated by at least two distinct histone modifications, polycomb-based histone H3 lysine 27 trimethylation (H3K27triM) and H3K9 dimethylation. The relationship between DNA hypermethylation and these histone modifications is not completely understood. Using chromatin immunoprecipitation microarrays (ChIP-chip) in prostate cancer cells compared to normal prostate, we found that up to 5% of promoters (16% CpG islands and 84% non-CpG islands) were enriched with H3K27triM. These genes were silenced specifically in prostate cancer, and those CpG islands affected showed low levels of DNA methylation. Downregulation of the EZH2 histone methyltransferase restored expression of the H3K27triM target genes alone or in synergy with histone deacetylase inhibition, without affecting promoter DNA methylation, and with no effect on the expression of genes silenced by DNA hypermethylation. These data establish EZH2-mediated H3K27triM as a mechanism of tumor-suppressor gene silencing in cancer that is potentially independent of promoter DNA methylation.

Prostate cancer is the most common malignancy in men in the USA and the second leading cause of cancer deaths. Fibroblast growth factors (FGFs), including FGF1 (acidic FGF), FGF2 (basic FGF), FGF6 and FGF8 are all expressed at increased levels in prostate cancer as paracrine and/or autocrine growth factors for the prostate cancer cells. In addition, increased mobilization of FGFs from the extracellular matrix in cancer tissues can increase the availability of FGFs to cancer cells. Prostate cancer epithelial cells express all four types of FGF receptors (FGFR-1 to -4) at variable frequencies. Expression of FGFR-1 and FGFR-4 is most closely linked to prostate cancer progression, while the role of FGFR-2 remains controversial. Activation of FGF receptors can activate multiple signal transduction pathways including the phospholipase Cg, phosphatidyl inositol 3-kinase, mitogenactivated protein kinase and signal transducers and activators of transcription (STAT) pathways, all of which play a role in prostate cancer progression. Sprouty proteins can negatively regulate FGF signal transduction, potentially limiting the impact of FGF signaling in prostate cancer, but in a significant fraction of prostate cancers there is decreased expression of Sprouty1 mRNA and protein. The effects of increased FGF receptor signaling are wide ranging and involve both the cancer cells and surrounding stroma, including the vasculature. The net result of increased FGF signaling includes enhanced proliferation, resistance to cell death, increased motility and invasiveness, increased angiogenesis, enhanced metastasis, resistance to chemotherapy and radiation and androgen independence, all of which can enhance tumor progression and clinical aggressiveness. For this reason, the FGF signaling system it is an attractive therapeutic target, particularly since therapies targeting FGF receptors and/or FGF signaling can affect both the tumor cells directly and tumor angiogenesis. A number of approaches that could target FGF receptors and/or FGF receptor signaling in prostate cancer are currently being developed.

The PTEN gene encodes a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase pathway and is inactivated in a wide variety of malignant neoplasms. High rates of loss of heterozygosity are observed at the 10q23.3 region containing the human PTEN gene in prostate cancer and other human malignancies, but the demonstrated rate of biallelic inactivation of the PTEN gene by mutation or homozygous deletion is significantly lower than the rate of loss of heterozygosity. The transgenic adenocarcinoma of mouse prostate model is a well characterized animal model of prostate cancer. Analysis of prostate cancer progression in transgenic adenocarcinoma of mouse prostate mice bred to Pten ؉/؊ heterozygous mice, coupled with analysis of the Pten gene and protein in the resulting tumors, reveals that haploinsufficiency of the Pten gene promotes the progression of prostate cancer in this model system. This observation provides a potential explanation for the discordance in rates of loss of heterozygosity at 10q23 and biallelic PTEN inactivation observed in prostate cancer and many human malignancies.T he PTEN tumor suppressor gene (also known as MMAC-1) encodes a phosphatase and is inactivated in a wide variety of human malignant neoplasms, including gliomas, melanomas, and carcinomas of the endometrium, kidney, breast, lung, upper respiratory tract, and prostate (1-4). The tumor suppressor activity of PTEN is thought to be primarily due to its ability to dephosphorylate phosphatidylinositol 3,4,5-phosphate at the 3-position and negatively regulate the activity of the phosphatidylinositol 3-kinase pathway (5, 6). A variety of biological effects have been attributed to loss of PTEN activity that are relevant to its role as a tumor suppressor gene, including enhanced cell proliferation (6), decreased apoptosis (5, 6), and increased tumor angiogenesis (7,8). The PTEN gene is also mutated in Cowden syndrome (9), a hereditary neoplastic syndrome characterized by an increased rate of thyroid cancer and breast cancer in affected females. Thus, the PTEN gene is an important tumor suppressor with a wide range of biological activities relevant to tumor progression.The PTEN tumor suppressor gene maps to human chromosome 10q23.3, and this region shows high rates of loss of heterozygosity (LOH) in a variety of human malignancies. Such LOH is usually due to the loss of relatively large areas of one copy of chromosome 10. It is generally believed that in the presence of such LOH the tumor suppressor gene present on the retained chromosome is inactivated by smaller deletions, resulting in homozygous deletion or by mutation. However, for the PTEN gene, the rate of LOH at 10q23.3 is often much higher than the apparent rate of inactivation of the retained PTEN allele. For example, LOH at 10q23.3 has been detected in 15-49% of clinically localized human prostate cancers, whereas mutation or homozygous deletion of the PTEN gene is detected in less than 10% of these same cases (4, 10-15). Similarly, LOH at 10q23 is present in m...