Epigenetic inactivation of the placentally imprinted tumor suppressor gene TFPI2 in prostate carcinoma.

Imprinted genes are often arranged in clusters epigenetically controlled by differentially methylated regions (DMR) containing bivalent histone modifications. Both DNA hypermethylation and hypomethylation in cancer can therefore disturb imprinted gene expression. We have studied expression, DNA methylation and histone modifications of TFPI2, a presumed tumor suppressor, and that of other genes in the 7q21 imprinted gene cluster in prostate cancer.TFPI, TFPI2, SGCE and PON2 expression were assessed by qRT-PCR in prostate cancer tissues and cell lines. DNA methylation and histone modifications were investigated by bisulphite sequencing and chromatin immunoprecipatation.TFPI2 was highly variably expressed in cancer tissues, in contrast to TFPI, and did not correlate to unchanged SGCE and significantly elevated PON2 expression. TFPI2 expression variations were unrelated to global DNA hypomethylation, but were associated with promoter methylation. PC3 cells with high expression retained normal methylation and bivalent histone modifications at DMR and promoter, whereas low-expressing LNCaP cells presented aberrant DNA methylation and more repressive histone modifications.Epigenetic disturbances in the 7q21 cluster affect imprinted genes in a non-coordinate manner suggesting an unstable epigenetic state prone to selection for specific expression changes.