BioProject

Members of bromodomain and extra-C terminal (BET) domain family and the histone deacetylase (HDAC) enzyme family efficiently regulate the expression of important oncogenes and tumor suppressors. More...

Members of bromodomain and extra-C terminal (BET) domain family and the histone deacetylase (HDAC) enzyme family efficiently regulate the expression of important oncogenes and tumor suppressors. HDACs induce histone hypoacetylation meanwhile BET proteins bind to acetylated lysines on histones to regulate gene transcription. Here we show that the BET inhibitor JQ1 inhibited proliferation and induced apoptosis of both triple negative and estrogen receptor positive breast cancer cells. Consistent with the critical role of histone acetylation in the regulation of gene expression, microarray analysis revealed broad transcriptional changes after JQ1 or HDAC inhibitor treatment. By examining the molecular pathways affected by the epigenetic inhibitors we found that both BET and HDAC inhibitors are suppressing similar genes that were involved in cell cycle regulation. Combining JQ1 with HDAC inhibitors, we found that the combination significantly decreased cell viability. This effect was partly mediated by the more efficient suppression of genes essential for cell-cycle progression. Furthermore, we detected a dramatic increase in the expression of several members of the USP17 family of deubiquitinating enzymes in response to the single agent treatment, which further increased by the combination treatment. Since constitutive expression of USP17 has been reported to block the Ras/MAPK pathway, our data also suggest that the blockade of the Ras/MAPK pathway might also be involved in the synergistic effect of the combination treatment. In conclusion, this study suggests that co-treatment with BET inhibitors and HDAC inhibitors could be an effective treatment regime in future breast cancer therapy. Overall design: MDA-MB-231 cells were treated with 1 µM JQ1 or 3.17 µM mocetinostat or with the combination of both for 48 hours. After treatment, total RNA was harvested, reverse transcribed and analyzed for gene expression by Affymetrix® Human Gene 2.1 ST Array. Three biological replicates were used for each group. Less...