title: Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells.
abstract: Studies on stem cell differentiation led to the identification of paused genes, characterized by the contemporary presence of both activator and repressor epigenetic markers (bivalent marking). TXNIP is an oncosuppressor gene the expression of which was reduced in breast cancer. In the present study, we evaluated whether the concept of epigenetic bivalent marking can be applied to TXNIP gene in breast cancer cells. Using chromatin immunoprecipitation (ChIP), three histone modifications were investigated: two associated with transcriptional activation, lysines 9-14 acetylation of H3 histone (H3K9K14ac) and lysine 4 trimethylation of H3 histone (H3K4me3), and one associated with transcriptional silencing, lysine 27 trimethylation of H3 histone (H3K27me3). According to the bivalent marking model, TXNIP gene appears to be paused in MDA157 cells (markers of active and repressed transcription are present), but are definitively silenced in MDA468 cells (presence of only markers of transcription repression). This was proven by evaluating TXNIP mRNA and protein levels after the treatment of cell lines with a histone deacetylase inhibitor (SAHA) and a poly-ADP-ribose polymerases inhibitor (PJ34). In MDA157 cells, SAHA and PJ34 showed a synergistic effect: a large increment was observed in TXNIP mRNA and protein levels. By contrast, in MDA468 cells, synergy between the two compounds was not observed. Therefore, the pausing epigenetic signature was permissive for synergy between SAHA and PJ34 on TXNIP gene expression. The synergy between SAHA and PJ34 on TXNIP expression was associated with variation in cell viability and apoptosis. In MDA157 cells, but not in MDA468 cells, combined treatment of SAHA and PJ34 induced a decrease in cell viability and an increase of apoptosis. Thus, our data support the hypothesis that TXNIP is an effective target for the treatment of breast cancer.
authors: Department of Medical and Biological Sciences, University of Udine, Italy.
authors: Federica
authors: F
authors: Baldan
authors: Department of Medical and Biological Sciences, University of Udine, Italy.
authors: Catia
authors: C
authors: Mio
authors: Department of Medical and Biological Sciences, University of Udine, Italy.
authors: Elisa
authors: E
authors: Lavarone
authors: Department of Medical and Biological Sciences, University of Udine, Italy.
authors: Carla
authors: C
authors: Di Loreto
authors: Department of Oncology, University Hospital 'S. Maria della Misericordia' Udine, Italy.
authors: Fabio
authors: F
authors: Puglisi
authors: Department of Medical and Biological Sciences, University of Udine, Italy.
authors: Giuseppe
authors: G
authors: Damante
authors: Department of Medical and Biological Sciences, University of Udine, Italy.
authors: Cinzia
authors: C
authors: Puppin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004357:Drug Synergism; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D016133:Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D056572:Histone Deacetylase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C486715:TXNIP protein, human