RANK (TNFRSF11A) Is Epigenetically Inactivated and Induces Apoptosis in Gliomas

摘要: Alterations of DNA methylation play an important role in gliomas. In a genome-wide screen, we identified CpG-rich fragment within the 5′ region tumor necrosis factor receptor superfamily, member 11A gene (TNFRSF11A) that showed de novo TNFRSF11A, also known as activator NF-κB (RANK), activates several signaling pathways, such NF-κB, JNK, ERK, p38α, and Akt/PKB. Using pyrosequencing, detected RANK/TNFRSF11A promoter 8 (57.1%) 14 diffuse astrocytomas, 17 (77.3%) 22 anaplastic 101 (84.2%) 120 glioblastomas, 6 (100%) glioma cell lines, 7 stem cell-enriched glioblastoma primary cultures but not four normal white matter tissue samples. Treatment lines with demethylating agent 5-aza-2′-deoxycytidine significantly reduced level resulted increased mRNA expression. Overexpression leads to significant reduction focus formation elevated apoptotic activity after flow cytometric analysis. Reporter assay studies transfected cells supported these results by showing activation pathways associated regulation apoptosis. We conclude is novel frequent target for gliomas, which affects thereby contributing molecular pathogenesis