Data from Methylation Silencing of Transforming Growth Factor-β Receptor Type II in Rat Prostate Cancers

Abstract

<div>Abstract<p>To identify methylation-silenced genes in prostate cancers, a microarray analysis for genes up-regulated by treatment with a demethylating agent, 5-aza-2′-deoxycytidine, was performed using three rat prostate cancer cell lines. Eight genes (<i>Aebp1, Dysf, Gas6, LOC361288, Nnat, Ocm, RGD1308119</i>, and <i>Tgfbr2</i>) were re-expressed at 16-fold or more, and their promoter CpG islands were shown to be densely methylated in the cancer cell lines. From the eight genes, <i>Tgfbr2</i>, a key mediator of transforming growth factor-β (TGF-β) signaling that has been strongly implicated in human and rat prostate carcinogenesis, was selected, and its silencing in primary samples was analyzed further. <i>Tgfbr2</i> was methylated and markedly down-regulated in three of seven 3,2′-dimethyl-4-aminobiphenyl–induced invasive adenocarcinomas in the dorsolateral lobe of the rat prostate. In humans, marked down-regulation of TGFBR2 protein was observed in 12 of 20 high-grade prostatic intraepithelial neoplasia and 36 of 60 prostate cancers. DNA methylation of the human <i>TGFBR2</i> promoter CpG islands repressed transcription, if present, but neither methylation nor mutation were detected in 27 human prostate cancers analyzed. Methylation silencing of rat <i>Tgfbr2</i> was associated with histone H3 lysine 9 trimethylation, whereas decreased expression of human <i>TGFBR2</i> was mainly due to decreased transcription activity, sometimes in concert with histone deacetylation and H3 lysine 27 trimethylation. The identification of methylation silencing of <i>Tgfbr2</i> in rat prostate cancers, in accordance with <i>TGFBR2</i> down-regulation in human prostate cancers, will enable us to analyze how aberrant methylation is induced <i>in vivo</i> and identify factors that promote and suppress the induction of aberrant methylation. [Cancer Res 2008;68(7):2112–21]</p></div>