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

Bryan E. Essien, Sinju Sundaresan, Ramon Ocadiz-Ruiz, Aaron Chavis, Amy C. Tsao, Arthur J. Tessier, Michael M. Hayes, Amanda Photenhauer, Milena Saqui-Salces, Anthony J. Kang, Yatrik M. Shah, Balazs Gyorffy, Juanita L. Merchant

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

In colorectal cancer, APC-mediated induction of unregulated cell growth involves posttranslational mechanisms that prevent proteasomal degradation of proto-oncogene β-catenin (CTNNB1) and its eventual translocation to the nucleus. However, about 10% of colorectal tumors also exhibit increased CTNNB1 mRNA. Here, we show in colorectal cancer 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 colorectal cancer. 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. Chromatin immunoprecipitation (ChIP) and EMSA identified a ZBP-89-binding site in the proximal promoter of CTNNB1. Reciprocally, 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.

Original languageEnglish (US)
Pages (from-to)6877-6887
Number of pages11
JournalCancer Research
Volume76
Issue number23
DOIs
StatePublished - Dec 1 2016

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    Essien, B. E., Sundaresan, S., Ocadiz-Ruiz, R., Chavis, A., Tsao, A. C., Tessier, A. J., Hayes, M. M., Photenhauer, A., Saqui-Salces, M., Kang, A. J., Shah, Y. M., Gyorffy, B., & Merchant, J. L. (2016). Transcription factor ZBP-89 drives a feedforward loop of β-catenin expression in colorectal cancer. Cancer Research, 76(23), 6877-6887. https://doi.org/10.1158/0008-5472.CAN-15-3150