Abstract 68: Increased H3K27 trimethylation is associated with decreased expression of miRNAs and bivalently modified genes in rhabdoid tumors

Abstract

Abstract Background: Rhabdoid tumors (RT) are aggressive tumors of infancy for which no effective treatment is currently available. These tumors are characterized by genetic loss of the SMARCB1 (SNF5, INI-1) component of the SWI/SNF chromatin remodeling complex. We previously reported an overall pattern of repression of genes associated with bivalent histone modification in embryonic stem cells within RT. We hypothesize that loss of SMARCB1 in RT results in an overall failure to release the repressive (H3K27) histone methylation in genes responsible for early differentiation. To test this hypothesis, we performed chromatin immunoprecipitation (ChIP) using antibodies specific for permissive (H3K4) and H3K27 trimethylation, comparing an RT cell line (G-410) with a human embryonic kidney cell line (HEK293). In addition, we report the global miRNA analysis of RT using the Illumina 96-sample Universal Matrix Array. Results: Those genes previously shown by others to be direct targets of SMARCB1 (PTN, CDK2NA, ATP1B1, HESR1, and FZD7) and genes previously shown to be down-regulated in RT (CDH2, SPON1, LEF1, SOX11, CDKN1B, SERPINE2, SPOCK1, DOCK4) all showed a significantly higher ratio of H3K27 methylation to H3K4 methylation (1.5-fold to 130-fold) in G410 cells compared with HEK293. In contrast, genes shown to have increased expression in RT (TFRC and DDX21) showed increased H3K4 methylation. Global miRNA analysis demonstrated striking downregulation of 156/158 (p<0.05) miRNAs compared with other pediatric renal tumors. ChIP analysis for H3K4 and H3K27 associated with miRNAs mir127, mir134, mir519e, mir99b, and mir152 likewise showed increased association with H3K27. Summary: Gene and miRNA expression strongly correlate with histone methylation patterns in the RT cell line. This suggests that loss of SMARCB1 in RTs results in striking repression of gene and miRNA expression which may be due to aberrant repressive (H3K27) histone methylation. The use of histone methylation inhibitors may therefore merit investigation for this pediatric tumor for which there is no effective therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 68. doi:10.1158/1538-7445.AM2011-68