NF-kappaB activation, dependent on acetylation/deacetylation, contributes to HIF-1 activity and migration of bone metastatic breast carcinoma cells.
Here, we show that NF-kappaB-HIF-1 interaction contributed to breast cancer metastatic capacity by means of an incomplete epithelial/mesenchymal transition and influencing migration, as shown in 1833 (human) and 4T1 (mouse) metastatic cells after different stimuli. The 1833 and the transforming growth factor-beta1-exposed 4T1 cells showed both epithelial (E-cadherins) and mesenchymal (N-cadherins and vimentin) markers, and common mechanisms contributed to the retention of certain epithelial characteristics and the control of migration. The complex NF-kappaB-HIF-1 reciprocal regulation and the enhanced c-Jun expression played a functional role in exacerbating the invasiveness of 1833 cells after p50/p65 transfection and of 4T1 cells exposed to transforming growth factor-beta1. Twist expression seemed to exert a permissive role also regulating epithelial/mesenchymal transition markers. After c-Src wild-type (Srcwt) transfection, c-Src-signal transducer overexpression in 1833 cells increased HIF-1 transactivating activity and invasiveness, and changed E-cadherin/N-cadherin ratio versus mesenchymal phenotype. The transcription factor pattern and the motile phenotype of metastatic 1833 cells were influenced by p65-lysine acetylation and HDAC-dependent epigenetic mechanisms, which positively regulated basal NF-kappaB and HIF-1 activities. However, HDAC3 acted as a corepressor of NF-kappaB activity in parental MDA-MB231 cells, thus explaining many differences from the derived 1833 clone, including reduced HIF-1alpha and c-Jun expression. Invasiveness was differently affected by HDAC knockdown in 1833 and MDA-MB231 cells. We suggest that acetylation/deacetylation are critical in establishing the bone-metastatic gene signature of 1833 cells by regulating the activity of NF-kappaB and HIF-1, and further clarify the epigenetic control of transcription factor network in the motile phenotype of 1833 cells.
Bendinelli
Paola
P
Dipartimento di Morfologia Umana e Scienze Biomediche Città Studi, University of Milan, Milan, Italy.
Matteucci
Emanuela
E
Maroni
Paola
P
Desiderio
Maria Alfonsina
MA
D000107:Acetylation; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004273:DNA, Neoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D010641:Phenotype; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src); D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D000099186:Histone Deacetylase 3
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D006655:Histone Deacetylases; D051793:Hypoxia-Inducible Factor 1; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D016392:Proto-Oncogene Proteins pp60(c-src); D000099186:Histone Deacetylase 3; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse