c-Src/histone deacetylase 3 interaction is crucial for hepatocyte growth factor dependent decrease of CXCR4 expression in highly invasive breast tumor cells.
Hepatocyte growth factor (HGF), a cytokine of tumor microenvironment, exerts opposite effects on CXCR4 expression in MCF-7 (low invasive) and MDA-MB231 (highly invasive) breast carcinoma cells, and here, we show that completely different molecular mechanisms downstream of c-Src activation were involved. As experimental models, we used cells transfected with two CXCR4 promoter constructs and treated with HGF or cotransfected with c-Src wild-type (Srcwt) expression vector; phospho-c-Src formation was enhanced in both cell lines. In MCF-7 cells, consistent with activations of CXCR4Luc constructs after HGF treatment and Srcwt expression, Ets1 and nuclear factor-kappaB (NF-kappaB) transcription factors were activated. In contrast, in MDA-MB231 cells, CXCR4Luc construct, Ets1 and NF-kappaB activities decreased. The divergence point seemed to be downstream of HGF/c-Src and consisted in the interaction between c-Src and the substrate histone deacetylase 3 (HDAC3). Only in MDA-MB231 cells, HDAC3 level was enhanced in membranes and nuclei 30 min after HGF and colocalized/coimmunoprecipitated with phospho-c-Src and phosphotyrosine. Thus, the CXCR4 induction by HGF in MCF-7 cells required NF-kappaB and Ets1 activations, downstream of phosphoinositide-3-kinase/Akt, whereas in HGF-treated MDA-MB231 cells, HDAC3 activation via c-Src probably caused a reduction of transcription factor activities, such as that of NF-kappaB. These results indicate possible roles of HGF in invasive growth of breast carcinomas. By enhancing CXCR4 in low invasive tumor cells, HGF probably favors their homing to secondary sites, whereas by suppressing CXCR4 in highly invasive cells, HGF might participate to retain them in the metastatic sites.
Matteucci
Emanuela
E
Institute of General Pathology, School of Medicine, University of Milan, via Luigi Mangiagalli, 31-20133 Milan, Italy.
Ridolfi
Elisa
E
Maroni
Paola
P
Bendinelli
Paola
P
Desiderio
Maria Alfonsina
MA
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D024202:Electrophoretic Mobility Shift Assay; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000099186:Histone Deacetylase 3
D017228:Hepatocyte Growth Factor; D006655:Histone Deacetylases; D016328:NF-kappa B; D016392:Proto-Oncogene Proteins pp60(c-src); D019718:Receptors, CXCR4; D000099186:Histone Deacetylase 3