Transcription Factor ZBP-89 Drives a Feedforward Loop of β-Catenin Expression in Colorectal Cancer.
Transcription Factor ZBP-89 Drives a Feedforward Loop of β-Catenin Expression in Colorectal Cancer.
复制标题
DOI：
10.1158/0008-5472.can-15-3150
复制
发表时间：
2016-12-01
期刊：
影响因子：
11.2
通讯作者：
Merchant JL
中科院分区：
文献类型：
--
作者：
Essien BE;Sundaresan S;Ocadiz-Ruiz R;Chavis A;Tsao AC;Tessier AJ;Hayes MM;Photenhauer A;Saqui-Salces M;Kang AJ;Shah YM;Győrffy B;Merchant JL
在结直肠癌（CRC）中，apc介导的不调节细胞生长的诱导涉及翻译后机制，该机制阻止原癌基因β-连环蛋白（CTNNB1）的蛋白酶体降解及其最终易位到细胞核。然而，大约10%的结直肠肿瘤也表现出CTNNB1 mRNA的增加。本研究表明，在结直肠癌中，编码转录因子ZBP-89的基因ZNF148的表达增加与患者生存率降低相关。组织阵列显示ZBP-89蛋白在结直肠癌早期过表达。在apc介导的肠息肉小鼠模型中条件缺失Zfp148表明，由于诱导Ctnnb1基因表达，ZBP-89是息肉形成所必需的。ChIP和EMSA在CTNNB1的近端启动子中发现了一个ZBP-89结合位点。相反，sirna介导的CTNNB1表达降低也降低了ZBP-89蛋白。ChIP在ZNF148启动子中发现了TCF DNA结合位点，Wnt信号通过该位点调控ZNF148基因表达。抑制ZNF148或CTNNB1均可减少wnt依赖型细胞系的集落形成，但不影响wnt依赖型细胞系的集落形成。因此，APC突变引发的细胞内β-catenin蛋白的增加是通过zbp -89介导的前馈诱导CTNNB1 mRNA来维持的。
In colorectal cancer (CRC), APC-mediated induction of unregulated cell growth involves post-translational mechanisms that prevent proteasomal degradation of proto-oncogene β-catenin (CTNNB1) and its eventual translocation to the nucleus. However, about 10 percent of colorectal tumors also exhibit increased CTNNB1 mRNA. Here we show in CRC that increased expression of ZNF148, the gene coding for transcription factor ZBP-89, correlated with reduced patient survival. Tissue arrays showed that ZBP-89 protein was overexpressed in the early stages of CRC. Conditional deletion of Zfp148 in a mouse model of Apc-mediated intestinal polyps demonstrated that ZBP-89 was required for polyp formation due to induction of Ctnnb1 gene expression. ChIP and EMSA identified a ZBP-89 binding site in the proximal promoter of CTNNB1. Recipricolly, siRNA-mediated reduction of CTNNB1 expression also decreased ZBP-89 protein. ChIP identified TCF DNA binding sites in the ZNF148 promoter through which Wnt signaling regulates ZNF148 gene expression. Suppression of either ZNF148 or CTNNB1 reduced colony formation in WNT-dependent, but not WNT-independent cell lines. Therefore, the increase in intracellular β–catenin protein initiated by APC mutations is sustained by ZBP-89-mediated feedforward induction of CTNNB1 mRNA.