1. ¹Department of Anatomy & Cell Biology and Shands Cancer Center, University of Florida, Gainesville, FL, USA
2. ²Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
3. ³The Wistar Institute, Philadelphia, PA, USA

Correspondence: Dr AM Ishov, Department of Anatomy & Cell Biology and Shands Cancer Center, University of Florida, 1376 Mowry Road, Room No. 358, Gainesville, FL 32610-3633, USA. E-mail: ishov@ufl.edu

Received 9 May 2007; Revised 13 September 2007; Accepted 20 September 2007; Published online 22 October 2007.

Abstract

The protooncogene c-met encodes the tyrosine kinase receptor for the hepatocyte growth factor/scatter factor (HGF/SF). While overexpression of c-met is documented in many types of tumors, the mechanism of c-met regulation remains elusive. Here, we demonstrate Daxx as a repressor of c-met transcription. The expression of c-met is elevated in Daxx knockout mouse cells and is reversed by Daxx reconstitution. C-met promoter analysis of Daxx^-/- cells reveled changes in chromatin acetylation, but not in DNA methylation. Daxx binds to the mouse c-met promoter and Daxx-binding region is sufficient for transcription repression, while HDAC2 is associated with c-met promoter mostly in Daxx^+/+ cells, pointing to Daxx-dependent HDAC2 recruitment as a potential mechanism of c-met repression. HGF-induced cell mobility and invasion confirmed augmented activity of c-Met/HGF pathway in Daxx^-/- cells. Finally, inverse correlation between Daxx and c-Met in cancer cell lines and in metastatic breast cancer specimens suggests potential function of Daxx as a c-met repressor during cancer progression.