Abstract 5214: Functional interaction between foxm1 and β-catenin

Abstract

Abstract The Wnt/β-catenin signaling pathway is aberrantly activated in human cancers and is critical for cancer formation, but its molecular mechanisms are not fully understood. In the current study, we found that FoxM1, which is also activated in most human tumors, is a novel downstream component of Wnt signaling and is critical for β-catenin transcriptional function in tumor cells. Wnt increases the level and nuclear translocation of FoxM1 through inhibition of FoxM1 protein degradation. FoxM1 binds directly to β-catenin and enhances β-catenin nuclear localization and transcriptional activity. Moreover, FoxM1, β-catenin and TCF-4 are mutually recruited to Wnt target-gene promoters, and FoxM1 promotes the assembly of the β-catenin-TCF transcription activation complex in the promoters hence the Wnt target gene expression. Furthermore, interaction of FoxM1 and β-catenin plays a critical role in glioma stem cell self-renewal and differentiation and is required for glioma formation. Finally, the expression levels of nuclear β-catenin in human GBM directly correlates with levels of nuclear FoxM1, supporting the critical role of FoxM1 in β-catenin activation in human GBM. Given the importance of FoxM1 and the Wnt/β-catenin signaling pathway in human cancers in general, our findings not only provide an improved understanding of the molecular mechanisms underlying Wnt/β-catenin activation and tumorigenesis but also suggest additional targets for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5214. doi:1538-7445.AM2012-5214