bal Reactivation of Epigenetically Silenced Genes Pr R rostate Cancer

wnloaded nscriptional silencing associated with aberrant promoter hypermethylation is a common anism of inactivation of tumor suppressor genes in cancer cells. To globally profile the genes ed by hypermethylation in prostate cancer, we screened a whole genome expression microarray nes reactivated in the LNCaP, DU-145, PC-3, and MDA2b prostate tumor cell lines after treatment the demethylating drug 5-aza-2-deoxycytidine and the histone deacetylation–inhibiting drug statin A. A total of 2,997 genes showed at least 2-fold upregulation of expression after drug ent in at least one prostate tumor cell line. For validation, we examined the first 45 genes, ranked regulation of expression, which had a typical CpG island and were known to be expressed in the l cell counterpart. Two important findings were, first, that several genes known to be frequently methylated in prostate cancer were apparent, and, second, that validation studies revealed eight genes hypermethylated in the prostate tumor cell lines, four of which were unmethylated in normal te cells and hypermethylated in primary prostate tumors (SLC15A3, 66%; KRT7, 54%; TACSTD2, GADD45b, 3%). Thus, we established the utility of our screen for genes hypermethylated in prostate r cells. One of the novel genes was TACSTD2/TROP2, a marker of human prostate basal cells stem cell characteristics. TACSTD2 was unmethylated in prostatic intraepithelial neoplasia ay have utility in emerging methylation-based prostate cancer tests. Further study of the and m hypermethylome will provide insight into the biology of the disease and facilitate translational studies in prostate cancer. Cancer Prev Res; 3(9); 1084–92. ©2010 AACR.