Epigenetic bivalent marking is permissive to the synergy of HDAC and PARP inhibitors on TXNIP expression in breast cancer cells

Abstract

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-ADPribose 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.

BET proteins regulate homologous recombination‐mediated DNA repair: BRCAness and implications for cancer therapy

“…Moreover, BET inhibition sensitizes HR‐proficient cancer cells to PARP inhibition, as represented by the decrease in cell viability. Previous attempts have been explored in order to sensitize TNBC cell to the action of PARP inhibitors (i.e., AZD2281 and PJ34) through the association with several epigenetic drugs, but results were discordant . In fact, Min et al .…”

MCM5 as a target of BET inhibitors in thyroid cancer cells

“…The ChIP assay was performed as previously described (Baldan et al, 2015). For immunoprecipitation, samples were incubated with 10 μg of rabbit polyclonal anti-BRD4 (Active Motif) or Rabbit IgG, (Millipore), as negative control.…”

TXNIP overexpression suppresses proliferation and induces apoptosis in SMMC7221 cells through ROS generation and MAPK pathway activation

“…A number of studies have confirmed that TXNIP shows strong growth suppressive, metastasis inhibitory and proapoptotic functions (13,14). Subsequently, it has been identified as a tumor suppressor gene in various hematological malignancies and solid tumors, such as breast cancer and thyroid cancer (15)(16)(17). Overexpression of TXNIP inhibited tumor growth and caused cell cycle arrest and apoptosis.…”