Abstract 2703: A direct regulation of Twist1 by FOXQ1 promotes colorectal cancer metastasis

Abstract Malignant cell transformation, invasion and metastasis are dependent on the coordinated rewiring of gene expression. A major component in the scaffold of these reprogramming events is one in which epithelial cells lose intercellular connections and polarity and adopt a motile mesenchymal phenotype, one that is largely supported by a robust transcriptional machinery consisting mostly of developmental transcription factors. We investigated the winged helix transcription factor, FOXQ1, identified from an oligonucleotide microarray expression analysis, as being concomitantly deregulated in both epithelial and stromal compartments. We found that FOXQ1 contributes to epithelial to mesenchymal transition (EMT), in part by directly affecting the transcription of Twist1, itself a key mediator of metastasis that transcriptionally regulates the expression of important molecules involved in EMT. Reporter gene assays and chromatin immunoprecipitation experiments showed that FOXQ1 regulated and directly interacted with the Twist1 promoter, leading to a suppression of E-cadherin and increased expression of mesenchymal markers. Forced expression and RNAi mediated silencing of FOXQ1 led to increased and decreased levels of Twist1 mRNA and protein levels, respectively, with concomitant effects on migration, invasion and in vivo metastasis of colorectal cancer cells. Moreover, FOXQ1 mRNA and protein expression correlated in a series of resected patient samples. Conclusively our results show that FOXQ1 is a novel mediator of colorectal cancer metastasis and joins the network of transcription factors that orchestrate EMT. Citation Format: Mohammed Abba, Nitin Patil, Kabeer Rasheed, Laura D. Nelson, Giridhar Mudduluru, Jörg H. Leupold, Heike Allgayer. A direct regulation of Twist1 by FOXQ1 promotes colorectal cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2703. doi:10.1158/1538-7445.AM2013-2703