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.
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.
复制标题
DOI：
10.1158/1541-7786.mcr-12-0390
复制
发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Weissman BE
中科院分区：
文献类型：
--
作者：
Kuwahara Y;Wei D;Durand J;Weissman BE
恶性横纹肌样瘤（MRT）是一种高度侵袭性的儿童癌症，在原发性肿瘤和细胞系中显示出hSNF 5/INI 1/SMARCB 1基因（SWI/SNF染色质重塑复合物的核心亚基）的失活或丢失。我们之前曾报道过，在一些MRT细胞系中，hSNF 5的重新表达以不依赖于p53的方式通过p21 CIP 1/WAF 1（p21）mRNA诱导导致G1期阻滞。然而，hSNF 5再表达激活基因转录的机制仍不清楚。我们最初通过询问hSNF 5丢失是否改变了其他共有p53靶基因的调控来寻找其他hSNF 5靶基因。我们的研究表明，hSNF 5只调节一个子集的p53靶基因，包括p21和NOXA，在MRT细胞系。我们还表明，hSNF 5的再表达调节SWI/SNF复合物的水平在转录起始位点（TSS）在两个位点，并导致激活的转录起始通过招募RNA聚合酶II（RNAPII）伴随H3 K4和H3 K36的修改。此外，我们的研究结果显示，与其他人肿瘤细胞系相比，MRT细胞系中的NOXA表达较低，这表明hSNF 5的缺失可能会改变这一重要凋亡基因的表达。因此，hSNF 5缺失后MRT发展的一种机制可能依赖于SWI/SNF复合物在关键基因启动子TSS处的染色质重塑活性降低。此外，由于我们观察到MRT细胞中NOXA表达后的生长抑制，NOXA途径可能为治疗这种侵袭性疾病提供具有临床相关性的新靶点。
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 p21CIP1/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.