SAFB1 Mediates Repression of Immune Regulators and Apoptotic Genes in Breast Cancer Cells
SAFB1 Mediates Repression of Immune Regulators and Apoptotic Genes in Breast Cancer Cells
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DOI：
10.1074/jbc.m109.066431
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发表时间：
2010-02-05
影响因子：
4.8
通讯作者：
Oesterreich, Steffi
中科院分区：
文献类型：
--
作者：
Hammerich-Hille, Stephanie;Kaipparettu, Benny A.;Oesterreich, Steffi
支架附着因子SAFB 1和SAFB 2是旁系同源物，其参与细胞周期调节、凋亡、分化和应激反应。它们已被证明作为雌激素受体辅抑制因子发挥作用，并且有证据表明在乳腺肿瘤发生中发挥作用。为了确定它们在MCF-7乳腺癌细胞中的内源性靶基因，我们利用了染色质免疫沉淀（ChIP）芯片和基因表达阵列研究的组合方法。通过在含有24，000个启动子的微阵列上进行ChIP芯片，我们在已知基因的启动子中鉴定了541个SAFB 1/SAFB 2结合位点，在1号和6号染色体上显著富集。基因表达分析表明，大多数靶基因在SAFB 1或SAFB 2的情况下被诱导，较少被抑制。有趣的是，通过ChIP芯片和基因表达阵列分析鉴定的基因之间没有显著的重叠，表明通过近端启动子外的区域进行调控。与SAFB 1共享大部分靶基因的SAFB 2不同，SAFB 1具有许多独特的靶基因，其中大多数参与免疫系统的调节。随后对雌激素治疗组的分析显示，12%的雌激素调节基因依赖于SAFB 1，其中大多数是雌激素抑制基因。这些主要是参与细胞凋亡的基因，如BBC 3，NEDD 9和OPG。因此，这项研究证实了SAFB 1/SAFB 2作为辅阻遏物的主要作用，也揭示了SAFB 1在免疫基因调节和雌激素介导的基因抑制中的一个先前未知的作用。
The scaffold attachment factors SAFB1 and SAFB2 are paralogs, which are involved in cell cycle regulation, apoptosis, differentiation, and stress response. They have been shown to function as estrogen receptor corepressors, and there is evidence for a role in breast tumorigenesis. To identify their endogenous target genes in MCF-7 breast cancer cells, we utilized a combined approach of chromatin immunoprecipitation (ChIP)-on-chip and gene expression array studies. By performing ChIP-on-chip on microarrays containing 24,000 promoters, we identified 541 SAFB1/SAFB2-binding sites in promoters of known genes, with significant enrichment on chromosomes 1 and 6. Gene expression analysis revealed that the majority of target genes were induced in the absence of SAFB1 or SAFB2 and less were repressed. Interestingly, there was no significant overlap between the genes identified by ChIP-on-chip and gene expression array analysis, suggesting regulation through regions outside the proximal promoters. In contrast to SAFB2, which shared most of its target genes with SAFB1, SAFB1 had many unique target genes, most of them involved in the regulation of the immune system. A subsequent analysis of the estrogen treatment group revealed that 12% of estrogen-regulated genes were dependent on SAFB1, with the majority being estrogen-repressed genes. These were primarily genes involved in apoptosis, such as BBC3, NEDD9, and OPG. Thus, this study confirms the primary role of SAFB1/SAFB2 as corepressors and also uncovers a previously unknown role for SAFB1 in the regulation of immune genes and in estrogen-mediated repression of genes.