Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells

Nobutake Yamamichi, Ken ichi Inada, Chihiro Furukawa, Kouhei Sakurai, Toshio Tando, Aya Ishizaka, Takeshi Haraguchi, Taketoshi Mizutani, Mitsuhiro Fujishiro, Ryoichi Shimomura, Masashi Oka, Masao Ichinose, Yutaka Tsutsumi, Masao Omata, Hideo Iba

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30 Citations (Scopus)

Abstract

In our recent study showing a correlation between Brm-deficiency and undifferentiated status of gastric cancer, we found that the Brm-type SWI/SNF complex is required for villin expression. To elucidate intestinal villin regulation more precisely, we here analyzed structure and function of the promoter of human villin. About 1.1 kb upstream of the determined major transcription start site, we identified a highly conserved region (HCR-Cdx) among mammals, which contains two binding sites for Cdx. Expression analyses of 30 human gastrointestinal cell lines suggested that villin is regulated by Cdx2. Introduction of Cdx family genes into colorectal SW480 cells revealed that villin is strongly induced strongly by Cdx2, moderately by Cdx1, and marginally by Cdx4. Knockdown of Cdx2 in SW480 cells caused a clear downregulation of villin, and reporter assays showed that HCR-Cdx is crucial for Cdx2-dependent and Brm-dependent villin expression. Immunohistochemical analyses of gastric intestinal metaplasia and cancer revealed that villin and Cdx2 expression are tightly coupled. GST pull-down assays demonstrated a direct interaction between Cdx2 and several SWI/SNF subunits. Chromatin immunoprecipitation analyses showed the recruitment of Cdx2 and Brm around HCR-Cdx. From these results, we concluded that Cdx2 regulates intestinal villin expression through recruiting Brm-type SWI/SNF complex to the villin promoter.

Original languageEnglish
Pages (from-to)1779-1789
Number of pages11
JournalExperimental Cell Research
Volume315
Issue number10
DOIs
Publication statusPublished - 10-06-2009

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Yamamichi, N., Inada, K. I., Furukawa, C., Sakurai, K., Tando, T., Ishizaka, A., Haraguchi, T., Mizutani, T., Fujishiro, M., Shimomura, R., Oka, M., Ichinose, M., Tsutsumi, Y., Omata, M., & Iba, H. (2009). Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells. Experimental Cell Research, 315(10), 1779-1789. https://doi.org/10.1016/j.yexcr.2009.01.006