title: Epigenetic control of endothelin-1 axis affects invasiveness of breast carcinoma cells with bone tropism.
abstract: Here, we report a complex regulation of endothelin-1 (ET-1) axis driven by epigenetic reactions in 1833-bone metastatic cells, emphasizing the importance in skeletal metastasis from breast carcinoma. Inhibitors of histone deacetylases, trichostatin A (TSA), and of DNA methylases, 5'-Azacytidine (Aza), caused, respectively, reduction and increase in 1833 cell invasiveness, without affecting the basal migration of parental MDA-MB231 cells. Of note, in the two cell lines exposed to Aza the blockade of the ET-1 receptor ETAR with BQ-123 oppositely changed invasive properties. Even if in MDA-MB231 cells the ET-1 axis was scarcely influenced by epigenetic reactions, ETAR remarkably decreased after Aza. In contrast, in 1833 cells Aza exposure enhanced ET-1 coupled to ETAR wild type, being also ETAR truncated form increased, and invasiveness was stimulated. Under demethylation, the increase in ET-1 steady state protein level in 1833 clone seemed regulated at transcriptional level principally via Ets1 transcription factor. In fact, actinomycin D almost completely prevented ET-1 mRNA induction due to Aza. Only in 1833 cells, TSA exposure inactivated ET-1 axis, with reduction of the expression of ET-1 and ETAR mutated form, in agreement with Matrigel invasion decrease. This treatment favoured the ET-1 repressional control, taking place at the level of mRNA stability due to the 3'-untranslated region in the ET-1 gene, and also decreased transcription via NF-kB. Environmental conditions that alter the balance between epigenetic reactions might, therefore, affect metastasis migratory mode influencing ET-1 axis.
authors: Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, via Luigi Mangiagalli, 31, 20133 Milano, Italy.
authors: Emanuela
authors: E
authors: Matteucci
authors: Istituto Ortopedico Galeazzi, IRCCS, Milano, Italy.
authors: Paola
authors: P
authors: Maroni
authors: Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, via Luigi Mangiagalli, 31, 20133 Milano, Italy.
authors: Paola
authors: P
authors: Bendinelli
authors: Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, via Luigi Mangiagalli, 31, 20133 Milano, Italy; Istituto FIRC di Oncologia Molecolare, Milano, Italy.
authors: Alessia
authors: A
authors: Locatelli
authors: Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, via Luigi Mangiagalli, 31, 20133 Milano, Italy. Electronic address: a.desiderio@unimi.it.
authors: Maria Alfonsina
authors: MA
authors: Desiderio
mesh_terms: D001374:Azacitidine / Q000494:pharmacology; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D019175:DNA Methylation; D003609:Dactinomycin / Q000494:pharmacology; D004338:Drug Combinations; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007797:Laminin / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D010456:Peptides, Cyclic / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004338:Drug Combinations; C494041:ETS1 protein, human; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007797:Laminin; D010456:Peptides, Cyclic; D011509:Proteoglycans; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; C059485:matrigel; D003609:Dactinomycin; C012589:trichostatin A; D003094:Collagen; D001374:Azacitidine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)