Transcription factor ZBP-89 drives a feedforward loop of beta-catenin expression in colorectal cancer

Essien, B. E. and Sundaresan, S. and Ocadiz-Ruiz, R. and Chavis, A. and Tsao, A. C. and Győrffy, Balázs (2016) Transcription factor ZBP-89 drives a feedforward loop of beta-catenin expression in colorectal cancer. CANCER RESEARCH, 76 (23). pp. 6877-6887. ISSN 0008-5472


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In colorectal cancer (CRC), APC-mediated induction of unregulated cell growth involves post-translational mechanisms that prevent proteasomal degradation of proto-oncogene beta-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 beta-catenin protein initiated by APC mutations is sustained by ZBP-89-mediated feedforward induction of CTNNB1 mRNA.

Item Type: Article
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: MTMT SWORD
Date Deposited: 24 Jan 2017 13:23
Last Modified: 01 Dec 2017 00:15

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