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First published online May 20, 2009
doi: 10.1242/10.1242/jcs.045278

Journal of Cell Science 122, 1895-1905 (2009)
Published by The Company of Biologists 2009
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Research Article

Blocking β-catenin binding to the ZBP1 promoter represses ZBP1 expression, leading to increased proliferation and migration of metastatic breast-cancer cells

Wei Gu1,*, Feng Pan2 and Robert H. Singer1,*

1 Department of Anatomy and Structural Biology, and Department of Cell Biology, Albert Einstein College of Medicine 1300 Morris Park Avenue, Bronx, NY 10461, USA
2 Molecular Neurobiology Program, Skirball Institute, New York University Medical Center, New York, NY 10012, USA

* Authors for correspondence (e-mails: wgu{at}aecom.yu.edu; rhsinger{at}aecom.yu.edu)

Accepted 10 February 2009

ZBP1 (zipcode-binding protein 1, also known as IMP-1) is an mRNA regulator, functioning in mRNA localization, stability and translational control. ZBP1 is actively expressed during embryogenesis and tumorigenesis, but its expression is repressed in metastatic breast-cancer cell lines and tumors. In this article, we show that downregulation of ZBP1 expression results from its promoter methylation, an epigenetic process that remodels the chromatin structure and frequently represses gene activity. Demethylation of the ZBP1 promoter in metastatic cells reactivated ZBP1 expression, owing to restoration of the interaction of the ZBP1 promoter with β-catenin. Loss of ZBP1 function not only increased growth ability of metastatic cells, but also promoted cell migration. We identified a number of mRNAs that were selectively associated with ZBP1 in breast-cancer cells. Many of these are involved in cell motility and in cell-cycle regulation, and displayed altered expression patterns in the absence of ZBP1. These data suggest that repression of ZBP1 deregulates its associated mRNAs, leading to the phenotypic changes of breast cancers.

Key words: ZBP1 repression, Promoter methylation, Wnt–β-catenin signaling, Cell proliferation, Metastasis


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