Regulation of c-met expression by transcription repressor Daxx.
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.
Morozov
V M
VM
Department of Anatomy & Cell Biology and Shands Cancer Center, University of Florida, Gainesville, FL, USA.
Massoll
N A
NA
Vladimirova
O V
OV
Maul
G G
GG
Ishov
A M
AM
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D056970:Co-Repressor Proteins; D019175:DNA Methylation; D018450:Disease Progression; D015536:Down-Regulation; D005786:Gene Expression Regulation; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000235:genetics
D002352:Carrier Proteins; D002843:Chromatin; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D019859:Proto-Oncogene Proteins c-met; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases