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Title: SNF5 reexpression in malignant rhabdoid tumors regulates transcription of target genes by recruitment of SWI/SNF complexes and RNAPII to the transcription start site of their promoters.

Authors: Kuwahara, Yasumichi; Wei, Darmood; Durand, Joel; Weissman, Bernard E

Published In Mol Cancer Res, (2013 Mar)

Abstract: Malignant rhabdoid tumor (MRT), a highly aggressive cancer of young children, displays inactivation or loss of the hSNF5/INI1/SMARCB1 gene, a core subunit of the SWI/SNF chromatin-remodeling complex, in primary tumors and cell lines. We have previously reported that reexpression of hSNF5 in some MRT cell lines causes a G1 arrest via p21(CIP1/WAF1) (p21) mRNA induction in a p53-independent manner. However, the mechanism(s) by which hSNF5 reexpression activates gene transcription remains unclear. We initially searched for other hSNF5 target genes by asking whether hSNF5 loss altered regulation of other consensus p53 target genes. Our studies show that hSNF5 regulates only a subset of p53 target genes, including p21 and NOXA, in MRT cell lines. We also show that hSNF5 reexpression modulates SWI/SNF complex levels at the transcription start site (TSS) at both loci and leads to activation of transcription initiation through recruitment of RNA polymerase II (RNAPII) accompanied by H3K4 and H3K36 modifications. Furthermore, our results show lower NOXA expression in MRT cell lines compared with other human tumor cell lines, suggesting that hSNF5 loss may alter the expression of this important apoptotic gene. Thus, one mechanism for MRT development after hSNF5 loss may rely on reduced chromatin-remodeling activity of the SWI/SNF complex at the TSS of critical gene promoters. Furthermore, because we observe growth inhibition after NOXA expression in MRT cells, the NOXA pathway may provide a novel target with clinical relevancy for treatment of this aggressive disease.

PubMed ID: 23364536 Exiting the NIEHS site

MeSH Terms: Brain Neoplasms/genetics*; Brain Neoplasms/metabolism; Brain Neoplasms/pathology; Cell Line, Tumor; Chromatin Assembly and Disassembly/genetics*; Chromosomal Proteins, Non-Histone/genetics*; Chromosomal Proteins, Non-Histone/metabolism; DNA-Binding Proteins/genetics*; DNA-Binding Proteins/metabolism; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms/genetics*; Kidney Neoplasms/metabolism; Kidney Neoplasms/pathology; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Promoter Regions, Genetic; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism; RNA Polymerase II/genetics*; RNA Polymerase II/metabolism; Rhabdoid Tumor/genetics*; Rhabdoid Tumor/metabolism; Rhabdoid Tumor/pathology; Transcription Factors/genetics*; Transcription Factors/metabolism; Transcription Initiation Site; Transcription, Genetic; Tumor Suppressor Protein p53/genetics*; Tumor Suppressor Protein p53/metabolism

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