Identification of PBX1 target genes in cancer cells by global mapping of PBX1 binding sites.
Identification of PBX1 target genes in cancer cells by global mapping of PBX1 binding sites.
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DOI：
10.1371/journal.pone.0036054
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang TL
中科院分区：
文献类型：
--
作者：
Thiaville MM;Stoeck A;Chen L;Wu RC;Magnani L;Oidtman J;Shih IeM;Lupien M;Wang TL
PBX1是一种参与器官发生和肿瘤发生的TALE同源结构域转录因子。虽然卵巢癌、乳腺癌和黑色素瘤细胞依赖PBX1生长和存活，但PBX1促进肿瘤发生的分子机制尚不清楚。本研究采用PBX1 ChIP-chip靶点与卵巢癌细胞中PBX1调控的转录组重叠的综合方法来鉴定转录受PBX1直接调控的基因。我们进一步确定在卵巢癌细胞中发现的PBX1靶基因是否与PBX1在癌组织中共过表达。通过分析来自卵巢浆液性癌的TCGA基因表达微阵列数据集，我们发现PBX1及其大量直接靶基因共同上调。在PBX1靶基因中，选择了一个同源结构域蛋白MEOX1进行功能分析，其DNA结合基序在PBX1免疫沉淀的DNA序列中富集。我们证明了MEOX1蛋白与PBX1蛋白相互作用，并且MEOX1的抑制产生与PBX1抑制相似的生长抑制表型。此外，异位表达的MEOX1在功能上挽救了PBX1的退出效应，表明MEOX1介导了PBX1的细胞生长信号。这些结果表明，MEOX1在卵巢癌中是PBX1的关键靶基因和辅助因子。
PBX1 is a TALE homeodomain transcription factor involved in organogenesis and tumorigenesis. Although it has been shown that ovarian, breast, and melanoma cancer cells depend on PBX1 for cell growth and survival, the molecular mechanism of how PBX1 promotes tumorigenesis remains unclear. Here, we applied an integrated approach by overlapping PBX1 ChIP-chip targets with the PBX1-regulated transcriptome in ovarian cancer cells to identify genes whose transcription was directly regulated by PBX1. We further determined if PBX1 target genes identified in ovarian cancer cells were co-overexpressed with PBX1 in carcinoma tissues. By analyzing TCGA gene expression microarray datasets from ovarian serous carcinomas, we found co-upregulation of PBX1 and a significant number of its direct target genes. Among the PBX1 target genes, a homeodomain protein MEOX1 whose DNA binding motif was enriched in PBX1-immunoprecipicated DNA sequences was selected for functional analysis. We demonstrated that MEOX1 protein interacts with PBX1 protein and inhibition of MEOX1 yields a similar growth inhibitory phenotype as PBX1 suppression. Furthermore, ectopically expressed MEOX1 functionally rescued the PBX1-withdrawn effect, suggesting MEOX1 mediates the cellular growth signal of PBX1. These results demonstrate that MEOX1 is a critical target gene and cofactor of PBX1 in ovarian cancers.
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