Malignant rhabdoid tumor: Epigenetic mechanism of tumorogen
This chapter explains the epigenetic mechanism of tumor formation in an aggressive and rare childhood malignancy, malignant rhabdoid tumors (MRT). In the majority of these tumors hSNF5/INI1 is inactivated via deletion or mutation. hSNF5/INI1 is a member of the ATP-dependent hSWI-SNF chromatin remodeling complex. This gene is a tumor suppressor gene. hSNF5 can function in both transcription activation and repression of genome. Re-expression of hSNF5 in MRT cells causes an accumulation in G0/G1, cellular senescence and apoptosis. Cellular senescence is largely the result of direct transcriptional activation of the tumorsuppressor p16INK4a by hSNF5. Whole genome expression profiling of hSNF5 cells revealed expression change of many E2F targets, including mitotic control genes and pre-replication complex. The balance between SWI/SNF activation and Polycomb group (PcG) silencing affects epigenetic control of the INK4b-ARF-INK4a locus in MRT cells. PcG proteins regulate higher order chromatin structure dynamically, to balance cell proliferation and differentiation. SWI/SNF mediates eviction of the Polycomb group repressive complex1 (PRC1) and Polycomb group repressive complex2 (PRC2) and extensive chromatin reprogramming.